|
1
|
Ninmer EK, Zhu H, Chianese-Bullock KA, von Mehren M, Haas NB, Ross MI, Dengel LT, Slingluff CL. Multipeptide vaccines for melanoma in the adjuvant setting: long-term survival outcomes and post-hoc analysis of a randomized phase II trial. Nat Commun 2024; 15:2570. [PMID: 38519525 PMCID: PMC10959948 DOI: 10.1038/s41467-024-46877-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Accepted: 03/13/2024] [Indexed: 03/25/2024] Open
Abstract
The critical roles of CD4+ T cells have been understudied for cancer vaccines. Here we report long-term clinical outcomes of a randomized multicenter phase II clinical trial (NCT00118274), where patients with high-risk melanoma received a multipeptide vaccine targeting CD8+ T cells (12MP) and were randomized to receive either of two vaccines for CD4+ (helper) T cells: 6MHP (6 melanoma-specific helper peptides), or tet (a nonspecific helper peptide from tetanus toxoid). Cyclophosphamide (Cy) pre-treatment was also assessed. Primary outcomes for T cell responses to 12MP, 6MHP, and tet were previously reported, suggesting immunogenicity of both vaccines but that CD8 T cell responses to 12MP were lower when tet was replaced with 6MHP. Here, in post-hoc analyses, we report durable prolongation of overall survival by adding 6MHP instead of tet. That benefit was experienced only by male patients. A favorable interaction of 6MHP and Cy is also suggested. Multivariable Cox regression analysis of the intent-to-treat population identify vaccine arm (12MP + 6MHP+Cy) and patient sex (male) as the two significant predictors of enhanced survival. These findings support the value of adding cognate T cell help to cancer vaccines and also suggest a need to assess the impact of patient sex on immune therapy outcomes.
Collapse
Affiliation(s)
- Emily K Ninmer
- Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, Charlottesville, VA, USA
| | - Hong Zhu
- Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
- University of Virginia, School of Medicine, Cancer Center, Charlottesville, VA, USA
| | - Kimberly A Chianese-Bullock
- Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, Charlottesville, VA, USA
- University of Virginia, School of Medicine, Cancer Center, Charlottesville, VA, USA
| | | | - Naomi B Haas
- Fox Chase Cancer Center, Philadelphia, PA, USA
- University of Pennsylvania, Philadelphia, PA, USA
| | - Merrick I Ross
- Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX, USA
| | - Lynn T Dengel
- Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, Charlottesville, VA, USA
| | - Craig L Slingluff
- Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, Charlottesville, VA, USA.
- University of Virginia, School of Medicine, Cancer Center, Charlottesville, VA, USA.
| |
Collapse
|
|
2
|
Bao K, Liang G, Tian T, Zhang X. Mathematical modeling of combined therapies for treating tumor drug resistance. Math Biosci 2024; 371:109170. [PMID: 38467302 DOI: 10.1016/j.mbs.2024.109170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Revised: 02/27/2024] [Accepted: 03/03/2024] [Indexed: 03/13/2024]
Abstract
Drug resistance is one of the most intractable issues to the targeted therapy for cancer diseases. To explore effective combination therapy schemes, we propose a mathematical model to study the effects of different treatment schemes on the dynamics of cancer cells. Then we characterize the dynamical behavior of the model by finding the equilibrium points and exploring their local stability. Lyapunov functions are constructed to investigate the global asymptotic stability of the model equilibria. Numerical simulations are carried out to verify the stability of equilibria and treatment outcomes using a set of collected model parameters and experimental data on murine colon carcinoma. Simulation results suggest that immunotherapy combined with chemotherapy contributes significantly to the control of tumor growth compared to monotherapy. Sensitivity analysis is performed to identify the importance of model parameters on the variations of model outcomes.
Collapse
Affiliation(s)
- Kangbo Bao
- School of Mathematics and Statistics, Central China Normal University, Wuhan, 430079, PR China.
| | - Guizhen Liang
- School of Mathematics and Information Science, Xinxiang University, Xinxiang, 453003, PR China.
| | - Tianhai Tian
- School of Mathematics, Monash University, Melbourne, VIC 3800, Australia.
| | - Xinan Zhang
- School of Mathematics and Statistics, Central China Normal University, Wuhan, 430079, PR China.
| |
Collapse
|
|
3
|
Markowski MC, Taplin ME, Aggarwal R, Sena LA, Wang H, Qi H, Lalji A, Sinibaldi V, Carducci MA, Paller CJ, Marshall CH, Eisenberger MA, Sanin DE, Yegnasubramanian S, Gomes-Alexandre C, Ozbek B, Jones T, De Marzo AM, Denmeade SR, Antonarakis ES. Bipolar androgen therapy plus nivolumab for patients with metastatic castration-resistant prostate cancer: the COMBAT phase II trial. Nat Commun 2024; 15:14. [PMID: 38167882 PMCID: PMC10762051 DOI: 10.1038/s41467-023-44514-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Accepted: 12/15/2023] [Indexed: 01/05/2024] Open
Abstract
Cyclic high-dose testosterone administration, known as bipolar androgen therapy (BAT), is a treatment strategy for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we report the results of a multicenter, single arm Phase 2 study (NCT03554317) enrolling 45 patients with heavily pretreated mCRPC who received BAT (testosterone cypionate, 400 mg intramuscularly every 28 days) with the addition of nivolumab (480 mg intravenously every 28 days) following three cycles of BAT monotherapy. The primary endpoint of a confirmed PSA50 response rate was met and estimated at 40% (N = 18/45, 95% CI: 25.7-55.7%, P = 0.02 one-sided against the 25% null hypothesis). Sixteen of the PSA50 responses were achieved before the addition of nivolumab. Secondary endpoints included objective response rate (ORR), median PSA progression-free survival, radiographic progression-free survival (rPFS), overall survival (OS), and safety/tolerability. The ORR was 24% (N = 10/42). Three of the objective responses occurred following the addition of nivolumab. After a median follow-up of 17.9 months, the median rPFS was 5.6 (95% CI: 5.4-6.8) months, and median OS was 24.4 (95% CI: 17.6-31.1) months. BAT/nivolumab was well tolerated, resulting in only five (11%) drug related, grade-3 adverse events. In a predefined exploratory analysis, clinical response rates correlated with increased baseline levels of intratumoral PD-1 + T cells. In paired metastatic tumor biopsies, BAT induced pro-inflammatory gene expression changes that were restricted to patients achieving a clinical response. These data suggest that BAT may augment antitumor immune responses that are further potentiated by immune checkpoint blockade.
Collapse
Affiliation(s)
- Mark C Markowski
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA.
| | - Mary-Ellen Taplin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Rahul Aggarwal
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Laura A Sena
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Hao Wang
- Division of Quantitative Sciences, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Hanfei Qi
- Division of Quantitative Sciences, Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Aliya Lalji
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Victoria Sinibaldi
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Michael A Carducci
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Channing J Paller
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Catherine H Marshall
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Mario A Eisenberger
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - David E Sanin
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Srinivasan Yegnasubramanian
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | | | - Busra Ozbek
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Tracy Jones
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Angelo M De Marzo
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA
| | - Samuel R Denmeade
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
| | - Emmanuel S Antonarakis
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD, USA
- Department of Medicine, Masonic Cancer Center, University of Minnesota Medical Center, Minneapolis, MN, USA
| |
Collapse
|
|
4
|
Mahashabde R, Bhatti SA, Martin BC, Painter JT, Rodriguez A, Ying J, Li C. Real-World Survival of First-Line Immune Checkpoint Inhibitor Treatment Versus Chemotherapy in Older Patients With Non-Small-Cell Lung Cancer and Synchronous Brain Metastases. JCO Oncol Pract 2023; 19:1009-1019. [PMID: 37729600 DOI: 10.1200/op.23.00042] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 06/14/2023] [Accepted: 07/13/2023] [Indexed: 09/22/2023] Open
Abstract
PURPOSE This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. METHODS Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. RESULTS The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). CONCLUSION Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.
Collapse
Affiliation(s)
- Ruchira Mahashabde
- Division of Pharmaceutical Evaluation and Policy, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Sajjad A Bhatti
- Department of Hematology and Medical Oncology, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Bradley C Martin
- Division of Pharmaceutical Evaluation and Policy, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Jacob T Painter
- Division of Pharmaceutical Evaluation and Policy, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Analiz Rodriguez
- Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Jun Ying
- Department of Biostatistics, University of Arkansas for Medical Sciences, Little Rock, AR
| | - Chenghui Li
- Division of Pharmaceutical Evaluation and Policy, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, AR
| |
Collapse
|
|
5
|
Kupersmith MJ, Jette N. Specific recommendations to improve the design and conduct of clinical trials. Trials 2023; 24:263. [PMID: 37038147 PMCID: PMC10084694 DOI: 10.1186/s13063-023-07276-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2022] [Accepted: 03/24/2023] [Indexed: 04/12/2023] Open
Abstract
There are many reasons why the majority of clinical trials fail or have limited applicability to patient care. These include restrictive entry criteria, short duration studies, unrecognized adverse drug effects, and reporting of therapy assignment preferential to actual use. Frequently, experimental animal models are used sparingly and do not accurately simulate human disease. We suggest two approaches to improve the conduct, increase the success, and applicability of clinical trials. Studies can apply dosing of the investigational therapeutics and outcomes, determined from animal models that more closely simulate human disease. More extensive identification of known and potential risk factors and confounding issues, gleaned from recently organized "big data," should be utilized to create models for trials. The risk factors in each model are then accounted for and managed during each study.
Collapse
Affiliation(s)
- Mark J Kupersmith
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
- Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
| | - Nathalie Jette
- Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Department of Population Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| |
Collapse
|
|
6
|
McCarthy PM, Valdera FA, Smolinsky TR, Adams AM, O’Shea AE, Thomas KK, Van Decar S, Carpenter EL, Tiwari A, Myers JW, Hale DF, Vreeland TJ, Peoples GE, Stojadinovic A, Clifton GT. Tumor infiltrating lymphocytes as an endpoint in cancer vaccine trials. Front Immunol 2023; 14:1090533. [PMID: 36960052 PMCID: PMC10029975 DOI: 10.3389/fimmu.2023.1090533] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Accepted: 02/14/2023] [Indexed: 03/09/2023] Open
Abstract
Checkpoint inhibitors have invigorated cancer immunotherapy research, including cancer vaccination. Classic early phase trial design and endpoints used in developing chemotherapy are not suited for evaluating all forms of cancer treatment. Peripheral T cell response dynamics have demonstrated inconsistency in assessing the efficacy of cancer vaccination. Tumor infiltrating lymphocytes (TILs), reflect the local tumor microenvironment and may prove a superior endpoint in cancer vaccination trials. Cancer vaccines may also promote success in combination immunotherapy treatment of weakly immunogenic tumors. This review explores the impact of TILs as an endpoint for cancer vaccination in multiple malignancies, summarizes the current literature regarding TILs analysis, and discusses the challenges of providing validity and a standardized implementation of this approach.
Collapse
Affiliation(s)
- Patrick M. McCarthy
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Franklin A. Valdera
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Todd R. Smolinsky
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
- *Correspondence: Todd R. Smolinsky, ; Elizabeth L. Carpenter,
| | - Alexandra M. Adams
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Anne E. O’Shea
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Katryna K. Thomas
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Spencer Van Decar
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Elizabeth L. Carpenter
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
- *Correspondence: Todd R. Smolinsky, ; Elizabeth L. Carpenter,
| | - Ankur Tiwari
- Department of Surgery, University of Texas Health Science Center, San Antonio, TX, United States
| | - John W. Myers
- Department of Surgery, Madigan Army Medical Center, Ft. Lewis, WA, United States
| | - Diane F. Hale
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | - Timothy J. Vreeland
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| | | | | | - Guy T. Clifton
- Department of Surgery, Brooke Army Medical Center, Ft. Sam Houston, TX, United States
| |
Collapse
|
|
7
|
Agostinetto E, Gligorov J, Piccart M. Systemic therapy for early-stage breast cancer: learning from the past to build the future. Nat Rev Clin Oncol 2022; 19:763-774. [PMID: 36253451 PMCID: PMC9575647 DOI: 10.1038/s41571-022-00687-1] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/26/2022] [Indexed: 11/23/2022]
Abstract
The treatment of breast cancer has improved dramatically over the past century, from a strictly surgical approach to a coordinated one, including local and systemic therapies. Systemic therapies for early-stage disease were initially tested against observation or placebo only in adjuvant trials. Subsequent clinical trials focusing on treatment 'fine-tuning' had a marked increase in cohort size, duration and costs, leading to a growing interest in the neoadjuvant setting in the past decade. Neoadjuvant trial designs have the advantages of enabling the direct evaluation of treatment effects on tumour diameter and offer unique translational research opportunities through the comparative analysis of tumour biology before, during and after treatment. Current technologies enabling the identification of better predictive biomarkers are shaping the new era of (neo)adjuvant trials. An urgent need exists to reinforce collaboration between the pharmaceutical industry and academia to share data and thus establish large databases of biomarker data coupled with patient outcomes that are easily accessible to the scientific community. In this Review, we summarize the evolution of (neo)adjuvant trials from the pre-genomic to the post-genomic era and provide critical insights into how neoadjuvant studies are currently designed, discussing the need for better end points and treatment strategies that are more personalized, including in the post-neoadjuvant setting.
Collapse
Affiliation(s)
- Elisa Agostinetto
- Institut Jules Bordet and l'Université Libre de Bruxelles, Brussels, Belgium
| | - Joseph Gligorov
- Institut Universitaire de Cancérologie AP-HP Sorbonne Université, Inserm U938, Cours St-Paul, Paris, France
| | - Martine Piccart
- Institut Jules Bordet and l'Université Libre de Bruxelles, Brussels, Belgium.
| |
Collapse
|
|
8
|
de Castria TB, Khalil DN, Harding JJ, O'Reilly EM, Abou-Alfa GK. Tremelimumab and durvalumab in the treatment of unresectable, advanced hepatocellular carcinoma. Future Oncol 2022; 18:3769-3782. [PMID: 36399155 DOI: 10.2217/fon-2022-0652] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Liver cancer is the third most common cause of cancer-related mortality worldwide, with over 780,000 deaths in 2018. About 90% of liver cancer cases are hepatocellular carcinoma (HCC), a prototype of inflammation-driven cancer, leading to a robust rationale for the exploration of immune therapy. Previously approved agents for first-line therapy, such as sorafenib, lenvatinib and bevacizumab combined with atezolizumab, have focused on angiogenesis. HIMALAYA was the first trial to demonstrate the benefit of dual immune checkpoint inhibitors, representing a new treatment option in this scenario.
Collapse
Affiliation(s)
| | - Danny N Khalil
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Weill Medical College at Cornell University, New York, NY 10021, USA
| | - James J Harding
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Weill Medical College at Cornell University, New York, NY 10021, USA
| | - Eileen M O'Reilly
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Weill Medical College at Cornell University, New York, NY 10021, USA
| | - Ghassan K Abou-Alfa
- Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Weill Medical College at Cornell University, New York, NY 10021, USA
| |
Collapse
|
|
9
|
C3d(g), iron nanoparticles, hemin and cytochrome c may induce oxidative cytotoxicity in tumors and reduce tumor-associated myeloid cells-mediated immunosuppression. Med Hypotheses 2022. [DOI: 10.1016/j.mehy.2022.110944] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
|
|
10
|
Weighted Log-Rank Test for Clinical Trials with Delayed Treatment Effect Based on a Novel Hazard Function Family. MATHEMATICS 2022. [DOI: 10.3390/math10152573] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In clinical trials with delayed treatment effect, the standard log-rank method in testing the difference between survival functions may have problems, including low power and poor robustness, so the method of weighted log-rank test (WLRT) is developed to improve the test performance. In this paper, a hyperbolic-cosine-shaped (CH) hazard function family model is proposed to simulate delayed treatment effect scenarios. Then, based on Fleming and Harrington’s method, this paper derives the corresponding weight function and its regular corrections, which are powerful in test, theoretically. Alternative methods of parameters selection based on potential information are also developed. Further, the simulation study is conducted to compare the power performance between CH WLRT, classical WLRT, modest weighted log-rank test and WLRT with logistic-type weight function under different hazard scenarios and simulation settings. The results indicate that the CH statistics are powerful and robust in testing the late difference, so the CH test is useful and meaningful in practice.
Collapse
|
|
11
|
Agostinetto E, Losurdo A, Nader-Marta G, Santoro A, Punie K, Barroso R, Popovic L, Solinas C, Kok M, de Azambuja V, Lambertini M. Progress and pitfalls in the use of immunotherapy for patients with triple negative breast cancer. Expert Opin Investig Drugs 2022; 31:567-591. [PMID: 35240902 DOI: 10.1080/13543784.2022.2049232] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
INTRODUCTION Triple negative breast cancer (TNBC) is an area of high unmet medical need in terms of new effective treatment strategies. Although breast cancer is traditionally considered a 'cold' tumor type, TNBC is the most appropriate subtype for immunotherapeutic strategies; this is due to the high level of tumor infiltrating lymphocytes, PD-L1 expression and tumor mutational burden relative to other breast cancer subtypes. AREAS COVERED This review examines the use of immunotherapeutic strategies in early and advanced TNBC. The paper summarizes data on novel promising immunomodulatory approaches that have been explored in early phase trials and discusses the pitfalls and limitations often encountered in clinical research. EXPERT OPINION PD-1-blockade is approved for stage II/III TNBC and for first-line treatment of PD-L1-positive TNBC patients with metastatic disease and should be considered standard of care. However, question marks and difficulties remain; these include the identification of predictive biomarkers to select patients who benefit from the addition of PD1-blockade and the balance between efficacy and long-term toxicity for an individual patient. Numerous treatment combinations and new immunotherapeutic strategies beyond PD1 blockade are being evaluated, thus reflecting a promising evolution of a more personalized approach, and extended clinical benefit in TNBC.
Collapse
Affiliation(s)
- Elisa Agostinetto
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium.,Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy
| | - Agnese Losurdo
- Humanitas Research Hospital - IRCCS, Humanitas Cancer Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Guilherme Nader-Marta
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium
| | - Armando Santoro
- Department of Biomedical Sciences, Humanitas University, via Rita Levi Montalcini 4, 20072 Pieve Emanuele, Milan, Italy.,Humanitas Research Hospital - IRCCS, Humanitas Cancer Center, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Kevin Punie
- Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium
| | | | - Lazar Popovic
- Oncology Institute of Vojvodina, Faculty of Medicine, University Novi Sad, Novi Sad, Serbia
| | - Cinzia Solinas
- Medical Oncology, ATS Sardegna, Ospedale San Francesco, Nuoro, Italy
| | - Marleen Kok
- Departments of Medical Oncology, Tumor Biology & Immunology. Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Vandro de Azambuja
- Academic Trials Promoting Team, Institut Jules Bordet and l'Université Libre de Bruxelles (U.L.B), Brussels, Belgium
| | - Matteo Lambertini
- Department of Internal Medicine and Medical Specialties (DiMI), School of Medicine, University of Genova, Genova, Italy.,Department of Medical Oncology, U.O.C Clinica di Oncologia Medica, IRCCS Ospedale Policlinico San Martino, Genova, Italy
| |
Collapse
|
|
12
|
Danzer MF, Terzer T, Berthold F, Faldum A, Schmidt R. Confirmatory adaptive group sequential designs for single-arm phase II studies with multiple time-to-event endpoints. Biom J 2022; 64:312-342. [PMID: 35152459 DOI: 10.1002/bimj.202000205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 05/26/2021] [Accepted: 05/30/2021] [Indexed: 11/07/2022]
Abstract
Existing methods concerning the assessment of long-term survival outcomes in one-armed trials are commonly restricted to one primary endpoint. Corresponding adaptive designs suffer from limitations regarding the use of information from other endpoints in interim design changes. Here we provide adaptive group sequential one-sample tests for testing hypotheses on the multivariate survival distribution derived from multi-state models, while making provision for data-dependent design modifications based on all involved time-to-event endpoints. We explicitly elaborate application of the methodology to one-sample tests for the joint distribution of (i) progression-free survival (PFS) and overall survival (OS) in the context of an illness-death model, and (ii) time to toxicity and time to progression while accounting for death as a competing event. Large sample distributions are derived using a counting process approach. Small sample properties are studied by simulation. An already established multi-state model for non-small cell lung cancer is used to illustrate the adaptive procedure.
Collapse
Affiliation(s)
- Moritz Fabian Danzer
- Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
| | - Tobias Terzer
- Division of Biostatistics, German Cancer Research Center, Heidelberg, Germany
| | - Frank Berthold
- Department of Pediatric Oncology and Hematology, Center for Integrated Oncology, University of Cologne, Cologne, Germany
| | - Andreas Faldum
- Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
| | - Rene Schmidt
- Institute of Biostatistics and Clinical Research, University of Münster, Münster, Germany
| |
Collapse
|
|
13
|
Chen J, Wang G, Zhang D, Luo X, Zhang D, Zhang Y. Construction of novel hypoxia-related gene model for prognosis and tumor microenvironment in endometrial carcinoma. Front Endocrinol (Lausanne) 2022; 13:1075431. [PMID: 36589842 PMCID: PMC9797861 DOI: 10.3389/fendo.2022.1075431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 12/02/2022] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Endometrial cancer is currently one of the three most common female reproductive cancers, which seriously threatens women's lives and health. Hypoxia disrupts the tumor microenvironment, thereby affecting tumor progression and drug resistance. METHODS We established hypoxia-related gene model to predict patient prognosis and 1-, 3-, and 5-year overall survival rates. Then, the expression level of hypoxia-related genes and survival data were extracted for comprehensive analysis by Cox regression analysis, and the model was established. RESULTS We analyzed the survival and prognosis of patients in the high and low-risk groups. The Kaplan-Meier curve showed that the low-risk group is associated with a better survival rate. The 1-, 3-, and 5-year AUC values of the model were 0.680, 0.698, and 0.687, respectively. Finally, we found that LAG3 may be a potential immune checkpoint for endometrial cancer. CONCLUSION We found four hypoxia-related genes (ANXA2, AKAP12, NR3C1, and GPI) associated with prognosis. The hypoxia-related gene model can also predict prognosis and tumor microenvironment in endometrial cancer.
Collapse
Affiliation(s)
- Junfeng Chen
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Guocheng Wang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Donghai Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Xiaomei Luo
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Da Zhang
- Department of Gynecological Oncology, Changchun Center Hospital, Changchun, Jilin, China
- *Correspondence: Yongli Zhang, ; Da Zhang,
| | - Yongli Zhang
- Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Yongli Zhang, ; Da Zhang,
| |
Collapse
|
|
14
|
Abstract
The role and use of independent data monitoring committees (IDMCs) has evolved over the past decades. The Food and Drug Administration and European Medicines Agency have issued guidelines on the role and functioning of such committees. In general, data monitoring committees are recommended for large, often randomised clinical trials involving life-threatening diseases, studies performed in vulnerable populations or where the experimental intervention can potentially harm the trial participant. Such committees play an important role in trials evaluating treatments with the potential to prolong life or reduce the risk of major adverse health outcomes.Typically, oncology clinical trials fall within these recommendations, as they are often large, randomised, multicentric protocols aiming at improving survival outcomes by exploring the use of study treatments that may be associated with a significant risk of serious, even life-threatening adverse events. IDMCs are required for National Cancer Institute phase III randomised trials, European Organisation for Research and Treatment of Cancer phase II/III trials with formal interim analyses, early-stopping rules or adaptive studies. The primary role of an IDMC of ensuring the safety of study participants and maintaining clinical trial integrity is particularly important in oncology trials, due to the nature of the disease, the potential for treatment toxicity and for instilling confidence that the clinical trial data are reliable. A clear understanding by IDMC members of the natural course of the disease, treatment landscape, importance and relevance of certain adverse events in trial participants, clinical trial methodology in general and stopping rules for oncology trials in particular, is crucial for the functioning of an IDMC.It is recommended that IDMC members should be experienced trialists, have a track record of strong clinical, statistical and/or methodological expertise and the required level of independence, as they play a highly important role in the protection of study participants, and in commercially and strategically important go/no decisions. Ideally, IDMC members should have relevant experience or have some training, mentorship or guidelines.
Collapse
Affiliation(s)
- P Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, KU Leuven, Leuven Cancer Institute, Leuven, Belgium
| |
Collapse
|
|
15
|
Peng SY, Chen L, Deng RH, Li H, Liu XH, Zheng DW, Wu CC, Liu CJ, Sun ZJ, Zhang XZ. Non-depleting reformation of immunosuppressive myeloid cells to broaden the application of anti-PD therapy. NANOSCALE 2021; 13:4420-4431. [PMID: 33616147 DOI: 10.1039/d1nr00830g] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Traditional methods of depleting tumor-associated myeloid cells via chemotherapy can easily lead to the re-recruitment of them, eventually resulting in chemo-resistance and presenting obstacles in immunotherapy. Herein, we report a nano-educator (NE) that when loaded with all trans retinoic acid (ATRA) and anti-PD-1 antibodies (aPD-1) instructs myeloid cells to assist T cells towards revitalizing anti-PD-1 therapy. In vivo, ATRA converts myeloid-derived suppressor cells (MDSCs) into dendritic cells (DCs), which are essential for anti-PD-1 therapy, while intervening in the polarization of macrophages. Furthermore, aPD-1-armed T cells reboot anti-tumor immunity after suppression relief, which exposes tumor-specific antigens and in turn promotes the maturation of transformed DCs. The nano-platform provides shelter for vulnerable immunomodulatory agents and durable drug release to stimulate intensive immune modulation. We established three types of tumor-bearing mice models with different myeloid cell contents to show the spatiotemporal complementarity of ATRA and aPD-1. The NE re-educates the tumor's guard to assist T cells in enhanced immunotherapy, broadening the application of aPD-1 in the treatment of anti-PD-1-resistant tumors.
Collapse
Affiliation(s)
- Si-Yuan Peng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Lei Chen
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China. and Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China
| | - Rong-Hui Deng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Hao Li
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China. and Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China
| | - Xin-Hua Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Di-Wei Zheng
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Cong-Cong Wu
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China. and Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China
| | - Chuan-Jun Liu
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| | - Zhi-Jun Sun
- The State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei-MOST) & Key Laboratory of Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China. and Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, P. R. China
| | - Xian-Zheng Zhang
- Key Laboratory of Biomedical Polymers of Ministry of Education, Department of Chemistry, Wuhan University, Wuhan 430072, P. R. China.
| |
Collapse
|
|
16
|
Kundu MG, Sarkar J. On information fraction for Fleming-Harrington type weighted log-rank tests in a group-sequential clinical trial design. Stat Med 2021; 40:2321-2338. [PMID: 33624861 DOI: 10.1002/sim.8905] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Revised: 12/29/2020] [Accepted: 01/21/2021] [Indexed: 11/07/2022]
Abstract
When comparing survival times of treatment and control groups under a more realistic nonproportional hazards scenario, the standard log-rank (SLR) test may be replaced by a more efficient weighted log-rank (WLR) test, such as the Fleming-Harrington (FH) test. Designing a group-sequential clinical trial with one or more interim looks during which a FH test will be performed, necessitates correctly quantifying the information fraction (IF). For SLR test, IF is defined simply as the ratio of interim to final numbers of events; but for FH test, it can deviate substantially from this ratio. In this article, we separate the effect of weight function (of FH test) alone on IF from the effect of censoring. We have shown that, without considering the effect of censoring, IF can be derived analytically for FH test using information available at the design stage and the additional effect due to censoring is relatively smaller. This article intends to serve two major purposes: first, to emphasize and rationalize the deviation of IF in weighted log-rank test from that of SLR test which is often overlooked (Jiménez, Stalbovskaya, and Jones); second, although it is impossible to predict IF for a weighted log-rank test at the design stage, our decomposition of effects on IF provides a reasonable and practically feasible range of IF to work with. We illustrate our approach with an example and provide simulation results to evaluate operating characteristics.
Collapse
Affiliation(s)
| | - Jyotirmoy Sarkar
- Indiana University-Purdue University Indianapolis, Indianapolis, Indiana, USA
| |
Collapse
|
|
17
|
Yu C, Huang X, Nian H, He P. A weighted log-rank test and associated effect estimator for cancer trials with delayed treatment effect. Pharm Stat 2021; 20:528-550. [PMID: 33427400 DOI: 10.1002/pst.2092] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 08/30/2020] [Accepted: 12/05/2020] [Indexed: 11/10/2022]
Abstract
The standard log-rank test has been extended by adopting various weight functions. Cancer vaccine or immunotherapy trials have shown a delayed onset of effect for the experimental therapy. This is manifested as a delayed separation of the survival curves. This work proposes new weighted log-rank tests to account for such delay. The weight function is motivated by the time-varying hazard ratio between the experimental and the control therapies. We implement a numerical evaluation of the Schoenfeld approximation (NESA) for the mean of the test statistic. The NESA enables us to assess the power and to calculate the sample size for detecting such delayed treatment effect and also for a more general specification of the non-proportional hazards in a trial. We further show a connection between our proposed test and the weighted Cox regression. Then the average hazard ratio using the same weight is obtained as an estimand of the treatment effect. Extensive simulation studies are conducted to compare the performance of the proposed tests with the standard log-rank test and to assess their robustness to model mis-specifications. Our tests outperform the Gρ,γ class in general and have performance close to the optimal test. We demonstrate our methods on two cancer immunotherapy trials.
Collapse
Affiliation(s)
- Chang Yu
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Xiang Huang
- Division of Epidemiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Hui Nian
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Philip He
- Biometrics and Information Sciences, AstraZeneca, Gaithersburg, Maryland, USA
| |
Collapse
|
|
18
|
Statistical adaptation to oncology drug development evolution. Contemp Clin Trials 2020; 99:106180. [PMID: 33164867 DOI: 10.1016/j.cct.2020.106180] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 09/25/2020] [Accepted: 10/15/2020] [Indexed: 01/18/2023]
Abstract
Cancer treatment started with surgery at least three thousand years ago. Radiation therapy was added in 1896 with chemotherapy started 50 years later. These "cut, burn, and poison" techniques try to kill cancer cells directly and have been the main approaches in treating cancer until recently. In the past few years, immunotherapies have revolutionized cancer treatment. Instead of treating the disease, immunotherapies treat the patient with the disease; more precisely, correct the patient's immune system so that it can fight cancer in a long term, which makes the cure of metastatic cancers a real possibility. To adapt to the evolution of oncology treatment, clinical trial designs and statistical analysis methodologies are required to change accordingly in order to efficiently bring novel oncology medicines to cancer patients. For example, one of the major differences between immunotherapies and chemotherapies is that immunotherapies may take longer to have an effect but generally last longer with some patients cured. Trial design assumptions and adaptation rules (if adaptive design is used) need to take account of this delayed effect and long-term cure effect phenomenon. At the same time, more efficient statistical tests such as Fleming-Harrington test and Zmax test can be used to improve statistical power over the conventional logrank test for the analyses of time-to-event data that often exhibit non-proportional hazards. This article intends to describe how oncology drug development evolves over time and how statistical methods change accordingly.
Collapse
|
|
19
|
Baxevanis CN, Fortis SP, Ardavanis A, Perez SA. Exploring Essential Issues for Improving Therapeutic Cancer Vaccine Trial Design. Cancers (Basel) 2020; 12:E2908. [PMID: 33050520 PMCID: PMC7600460 DOI: 10.3390/cancers12102908] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2020] [Revised: 10/07/2020] [Accepted: 10/09/2020] [Indexed: 12/24/2022] Open
Abstract
Therapeutic cancer vaccines have been at the forefront of cancer immunotherapy for more than 20 years, with promising results in phase I and-in some cases-phase II clinical trials, but with failures in large phase III studies. After dozens of clinical studies, only Dendreon's dendritic cell vaccine Sipuleucel-T has succeeded in receiving US FDA approval for the treatment of metastatic castrate-resistant prostate cancer. Although scientists working on cancer immunotherapy feel that this is an essential breakthrough for the field, they still expect that new vaccine regimens will yield better clinical benefits compared to the four months prolonged median overall survival (OS) Sipuleucel-T demonstrated in the IMPACT phase III clinical trial. Clinical development of cancer vaccines has been unsuccessful due to failures either in randomized phase II or-even worse-phase III trials. Thus, rigorous re-evaluation of these trials is urgently required in order to redefine aspects and optimize the benefits offered by therapeutic cancer vaccines. The scope of this review is to provide to the reader our thoughts on the key challenges in maximizing the therapeutic potentials of cancer vaccines, with a special focus on issues that touch upon clinical trial design.
Collapse
Affiliation(s)
- Constantin N. Baxevanis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
| | - Sotirios P. Fortis
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
| | - Alexandros Ardavanis
- 1st Medical Oncology Clinic, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece;
| | - Sonia A. Perez
- Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, 171 Alexandras Avenue, 11522 Athens, Greece; (S.P.F.); (S.A.P.)
| |
Collapse
|
|
20
|
Centanni M, Moes DJAR, Trocóniz IF, Ciccolini J, van Hasselt JGC. Clinical Pharmacokinetics and Pharmacodynamics of Immune Checkpoint Inhibitors. Clin Pharmacokinet 2020; 58:835-857. [PMID: 30815848 PMCID: PMC6584248 DOI: 10.1007/s40262-019-00748-2] [Citation(s) in RCA: 222] [Impact Index Per Article: 44.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Immune checkpoint inhibitors (ICIs) have demonstrated significant clinical impact in improving overall survival of several malignancies associated with poor outcomes; however, only 20–40% of patients will show long-lasting survival. Further clarification of factors related to treatment response can support improvements in clinical outcome and guide the development of novel immune checkpoint therapies. In this article, we have provided an overview of the pharmacokinetic (PK) aspects related to current ICIs, which include target-mediated drug disposition and time-varying drug clearance. In response to the variation in treatment exposure of ICIs and the significant healthcare costs associated with these agents, arguments for both dose individualization and generalization are provided. We address important issues related to the efficacy and safety, the pharmacodynamics (PD), of ICIs, including exposure–response relationships related to clinical outcome. The unique PK and PD aspects of ICIs give rise to issues of confounding and suboptimal surrogate endpoints that complicate interpretation of exposure–response analysis. Biomarkers to identify patients benefiting from treatment with ICIs have been brought forward. However, validated biomarkers to monitor treatment response are currently lacking.
Collapse
Affiliation(s)
- Maddalena Centanni
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands
| | - Dirk Jan A R Moes
- Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, Leiden, The Netherlands
| | - Iñaki F Trocóniz
- Pharmacometrics and Systems Pharmacology, Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain
| | - Joseph Ciccolini
- SMARTc, CRCM Inserm U1068 Aix Marseille Univ and La Timone University Hospital of Marseille, Marseille, France
| | - J G Coen van Hasselt
- Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.
| |
Collapse
|
|
21
|
Chu C, Liu S, Rong A. Study design of single-arm phase II immunotherapy trials with long-term survivors and random delayed treatment effect. Pharm Stat 2020; 19:358-369. [PMID: 31930622 DOI: 10.1002/pst.1976] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2018] [Revised: 08/28/2019] [Accepted: 09/09/2019] [Indexed: 01/25/2023]
Abstract
In the traditional study design of a single-arm phase II cancer clinical trial, the one-sample log-rank test has been frequently used. A common practice in sample size calculation is to assume that the event time in the new treatment follows exponential distribution. Such a study design may not be suitable for immunotherapy cancer trials, when both long-term survivors (or even cured patients from the disease) and delayed treatment effect are present, because exponential distribution is not appropriate to describe such data and consequently could lead to severely underpowered trial. In this research, we proposed a piecewise proportional hazards cure rate model with random delayed treatment effect to design single-arm phase II immunotherapy cancer trials. To improve test power, we proposed a new weighted one-sample log-rank test and provided a sample size calculation formula for designing trials. Our simulation study showed that the proposed log-rank test performs well and is robust of misspecified weight and the sample size calculation formula also performs well.
Collapse
Affiliation(s)
- Chenghao Chu
- Department of Biostatistics, Indiana University, Fairbanks School of Public Health, Indianapolis, IN, U.S.A
| | - Shufang Liu
- Data Science, Astellas Pharma Inc, Northbrook, IL, U.S.A
| | - Alan Rong
- Data Science, Astellas Pharma Inc, Northbrook, IL, U.S.A
| |
Collapse
|
|
22
|
Westdorp H, Creemers JHA, van Oort IM, Schreibelt G, Gorris MAJ, Mehra N, Simons M, de Goede AL, van Rossum MM, Croockewit AJ, Figdor CG, Witjes JA, Aarntzen EHJG, Mus RDM, Brüning M, Petry K, Gotthardt M, Barentsz JO, de Vries IJM, Gerritsen WR. Blood-derived dendritic cell vaccinations induce immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer. J Immunother Cancer 2019; 7:302. [PMID: 31727154 PMCID: PMC6854814 DOI: 10.1186/s40425-019-0787-6] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Accepted: 10/22/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived CD1c+ myeloid dendritic cells (mDCs; cDC2) and plasmacytoid DCs (pDCs). METHODS In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and overall survival. Radiological responses were assessed by MRIs and contrast-enhanced 68Ga-prostate-specific membrane antigen PET/CT, according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. RESULTS Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) antigen specific T cells were detected more frequently in skin biopsies of patients with radiological non-progressive disease (5/13 patients; 38%) compared to patients with progressive disease (0/8 patients; 0%). In these patients with vaccination enhanced dm+ and IFN-γ+ antigen-specific T cells median rPFS was 18.8 months (n = 5) vs. 5.1 months (n = 16) in patients without IFN-γ-producing antigen-specific T cells (p = 0.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. CONCLUSIONS Immunotherapy with blood-derived DC subsets was feasible and safe and induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with an improved clinical outcome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02692976, registered 26 February 2016, retrospectively registered.
Collapse
Affiliation(s)
- Harm Westdorp
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands.,Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands
| | - Jeroen H A Creemers
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands
| | - Inge M van Oort
- Department of Urology, Radboudumc, Nijmegen, The Netherlands
| | - Gerty Schreibelt
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands
| | - Mark A J Gorris
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands
| | - Niven Mehra
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands.,Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands
| | - Michiel Simons
- Department of Pathology, Radboudumc, Nijmegen, The Netherlands
| | - Anna L de Goede
- Department of Pharmacy, Radboudumc, Nijmegen, The Netherlands
| | | | | | - Carl G Figdor
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands
| | - J Alfred Witjes
- Department of Urology, Radboudumc, Nijmegen, The Netherlands
| | - Erik H J G Aarntzen
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Roel D M Mus
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | | | - Katja Petry
- Miltenyi Biotec GmbH, Bergisch Gladbach, Germany
| | - Martin Gotthardt
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - Jelle O Barentsz
- Department of Radiology and Nuclear Medicine, Radboudumc, Nijmegen, The Netherlands
| | - I Jolanda M de Vries
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands. .,Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands.
| | - Winald R Gerritsen
- Department of Tumor Immunology and Medical Oncology, Radboud Institute for Molecular Life Sciences, Radboudumc, Geert Grooteplein 26, 6525 GA, Nijmegen, The Netherlands.,Department of Medical Oncology, Radboudumc, Nijmegen, The Netherlands
| |
Collapse
|
|
23
|
Lanitis T, Ambavane A, Zheng Y, Schlichting M, Phatak H. Value assessment of immuno-oncology in the treatment of rare tumors in the era of accelerated conditional approvals. Future Oncol 2019; 15:4057-4067. [PMID: 31687852 DOI: 10.2217/fon-2019-0456] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Aim: To conduct a value assessment of an immuno-oncology (IO) therapy for a rare cancer and evaluate whether existing frameworks consider challenges associated with valuing IOs for rare cancers. Materials & methods: Value frameworks developed by American Society of Clinical Oncologists, Memorial Sloan Kettering Cancer Center and National Comprehensive Cancer Network were used to estimate the value of an IO therapy in a rare cancer based on single-arm trial data and retrospective studies. Results: Paucity of direct evidence comparing rare cancer treatments and lack of acceptance of indirect comparisons hinder appropriate value assessment. Measurement of value based on short-term outcomes may not capture the value of IOs, where survival is often characterized by a plateau. Conclusion: Further work is required to factor in nuances associated with rare cancers and guide end users of the frameworks. To capture true value, multiple or more holistic value assessments are required.
Collapse
Affiliation(s)
- Tereza Lanitis
- Evidera, The Ark, 201 Talgarth Road, Hammersmith, London W6 8BJ, United Kingdom
| | - Apoorva Ambavane
- Evidera, The Ark, 201 Talgarth Road, Hammersmith, London W6 8BJ, United Kingdom
| | - Ying Zheng
- EMD Serono Inc, One Technology Place, Rockland, MA 02370, USA
| | | | - Hemant Phatak
- EMD Serono Inc, One Technology Place, Rockland, MA 02370, USA
| |
Collapse
|
|
24
|
In Vivo Administration of Recombinant Human Granulocyte Colony-Stimulating Factor Increases the Immune Effectiveness of Dendritic Cell-Based Cancer Vaccination. Vaccines (Basel) 2019; 7:vaccines7030120. [PMID: 31546936 PMCID: PMC6789603 DOI: 10.3390/vaccines7030120] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2019] [Revised: 09/12/2019] [Accepted: 09/17/2019] [Indexed: 01/01/2023] Open
Abstract
Significant recent advances in cancer immunotherapeutics include the vaccination of cancer patients with tumor antigen-associated peptide-pulsed dendritic cells (DCs). DC vaccines with homogeneous, mature, and functional activities are required to achieve effective acquired immunity; however, the yield of autologous monocyte-derived DCs varies in each patient. Priming with a low dose of recombinant human granulocyte colony-stimulating factor (rhG-CSF) 16-18 h prior to apheresis resulted in 50% more harvested monocytes, with a significant increase in the ratio of CD11c+CD80+ DCs/apheresed monocytes. The detection of antigen-specific cytotoxic T lymphocytes after Wilms' tumor 1-pulsed DC vaccination was higher in patients treated with rhG-CSF than those who were not, based on immune monitoring using tetramer analysis. Our study is the first to report that DC vaccines for cancer immunotherapy primed with low-dose rhG-CSF are expected to achieve higher acquired immunogenicity.
Collapse
|
|
25
|
Beyer U, Dejardin D, Meller M, Rufibach K, Burger HU. A multistate model for early decision‐making in oncology. Biom J 2019; 62:550-567. [DOI: 10.1002/bimj.201800250] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2018] [Revised: 05/15/2019] [Accepted: 05/15/2019] [Indexed: 01/13/2023]
Affiliation(s)
- Ulrich Beyer
- Department of Biostatistics MDBB 663, F. Hoffmann‐La Roche Ltd. Basel Switzerland
| | - David Dejardin
- Department of Biostatistics MDBB 663, F. Hoffmann‐La Roche Ltd. Basel Switzerland
| | - Matthias Meller
- Department of Biostatistics MDBB 663, F. Hoffmann‐La Roche Ltd. Basel Switzerland
| | - Kaspar Rufibach
- Department of Biostatistics MDBB 663, F. Hoffmann‐La Roche Ltd. Basel Switzerland
| | - Hans Ulrich Burger
- Department of Biostatistics MDBB 663, F. Hoffmann‐La Roche Ltd. Basel Switzerland
| |
Collapse
|
|
26
|
Abstract
Delayed separation in survival curves has been observed in immuno-oncology clinical trials. Under this situation, the classic log-rank test may confront high power loss. In this paper, we consider a Zmax test, which is the maximum of the log-rank test and a Fleming-Harrington test. Simulation studies indicate that the Zmax test not only controls the Type I error rate but also maintains good power under different delayed effect models. The asymptotic properties of the Zmax test are also established, which further supports its robustness. We apply the Zmax test to two data sets reported in recent immuno-oncology clinical trials, in which Zmax has exhibited remarkable improvement over the conventional log-rank test.
Collapse
Affiliation(s)
- Miao Yang
- Department of Biometrics, Data Science and Systems, Nektar Therapeutics, San Francisco, CA, USA
| | - Zhaowei Hua
- Department of Data Sciences & Statistics, Alnylam Pharmaceuticals Inc, Cambridge, MA, USA
| | - Lan Xue
- Department of Statistics, Oregon State University, Corvallis, OR, USA
| | - Mingxiu Hu
- Department of Biometrics, Data Science and Systems, Nektar Therapeutics, San Francisco, CA, USA
| |
Collapse
|
|
27
|
Leshem Y, Pastan I. Pseudomonas Exotoxin Immunotoxins and Anti-Tumor Immunity: From Observations at the Patient's Bedside to Evaluation in Preclinical Models. Toxins (Basel) 2019; 11:toxins11010020. [PMID: 30621280 PMCID: PMC6356957 DOI: 10.3390/toxins11010020] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Revised: 01/04/2019] [Accepted: 01/04/2019] [Indexed: 01/05/2023] Open
Abstract
Immunotoxins are protein drugs composed of a targeting domain genetically fused to a protein toxin. One killing domain being explored is a truncated Pseudomonas exotoxin A (PE). PE based immunotoxins are designed to kill cells directly by inhibiting their ability to synthesize proteins. However, observations from clinical trials suggest that this alone cannot explain their anti-tumor activity. Here we discuss patterns of clinical responses suggesting that PE immunotoxins can provoke anti-tumor immunity, and review murine models that further support this ability. In addition, we describe our preclinical effort to develop a combination therapy of local PE immunotoxins with a systemic anti-CTLA-4 immune check point blocking antibody. The combination eradicated murine tumors and prolonged the survival of mice. Clinical trials that test the ability of immunotoxins to augment immunotherapy have been recently opened.
Collapse
Affiliation(s)
- Yasmin Leshem
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
- Laboratory of Molecular Immunology, Faculty of Biology and Technion Integrated Cancer Center, Technion-Israel Institute of Technology, Haifa 3200003, Israel.
| | - Ira Pastan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
| |
Collapse
|
|
28
|
A structural methodology for modeling immune-tumor interactions including pro- and anti-tumor factors for clinical applications. Math Biosci 2018; 304:48-61. [PMID: 30055212 DOI: 10.1016/j.mbs.2018.07.006] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 07/10/2018] [Accepted: 07/17/2018] [Indexed: 12/17/2022]
Abstract
The immune system turns out to have both stimulatory and inhibitory factors influencing on tumor growth. In recent years, the pro-tumor role of immunity factors such as regulatory T cells and TGF-β cytokines has specially been considered in mathematical modeling of tumor-immune interactions. This paper presents a novel structural methodology for reviewing these models and classifies them into five subgroups on the basis of immune factors included. By using our experimental data due to immunotherapy experimentation in mice, these five modeling groups are evaluated and scored. The results show that a model with a small number of variables and coefficients performs efficiently in predicting the tumor-immune system interactions. Though immunology theorems suggest to employ a larger number of variables and coefficients, more complicated models are here shown to be inefficient due to redundant parallel pathways. So, these models are trapped in local minima and restricted in prediction capability. This paper investigates the mathematical models that were previously developed and proposes variables and pathways that are essential for modeling tumor-immune. Using these variables and pathways, a minimal structure for modeling tumor-immune interactions is proposed for future studies.
Collapse
|
|
29
|
Subbiah V, Murthy R, Hong DS, Prins RM, Hosing C, Hendricks K, Kolli D, Noffsinger L, Brown R, McGuire M, Fu S, Piha-Paul S, Naing A, Conley AP, Benjamin RS, Kaur I, Bosch ML. Cytokines Produced by Dendritic Cells Administered Intratumorally Correlate with Clinical Outcome in Patients with Diverse Cancers. Clin Cancer Res 2018; 24:3845-3856. [PMID: 30018119 DOI: 10.1158/1078-0432.ccr-17-2707] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 02/05/2018] [Accepted: 05/07/2018] [Indexed: 01/08/2023]
Abstract
Purpose: Dendritic cells (DC) initiate adaptive immune responses through the uptake and presentation of antigenic material. In preclinical studies, intratumorally injected activated DCs (aDCs; DCVax-Direct) were superior to immature DCs in rejecting tumors from mice.Experimental Design: This single-arm, open-label phase I clinical trial evaluated the safety and efficacy of aDCs, administered intratumorally, in patients with solid tumors. Three dose levels (2 million, 6 million, and 15 million aDCs per injection) were tested using a standard 3 + 3 dose-escalation trial design. Feasibility, immunogenicity, changes to the tumor microenvironment after direct injection, and survival were evaluated. We also investigated cytokine production of aDCs prior to injection.Results: In total, 39 of the 40 enrolled patients were evaluable. The injections of aDCs were well tolerated with no dose-limiting toxicities. Increased lymphocyte infiltration was observed in 54% of assessed patients. Stable disease (SD; best response) at week 8 was associated with increased overall survival. Increased secretion of interleukin (IL)-8 and IL12p40 by aDCs was significantly associated with survival (P = 0.023 and 0.024, respectively). Increased TNFα levels correlated positively with SD at week 8 (P < 0.01).Conclusions: Intratumoral aDC injections were feasible and safe. Increased production of specific cytokines was correlated with SD and prolonged survival, demonstrating a link between the functional profile of aDCs prior to injection and patient outcomes. Clin Cancer Res; 24(16); 3845-56. ©2018 AACR.
Collapse
Affiliation(s)
- Vivek Subbiah
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Ravi Murthy
- Department of Interventional Radiology, Division of Radiology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David S Hong
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert M Prins
- Department of Neurosurgery, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California
| | - Chitra Hosing
- Department of Stem Cell Transplantation, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | | | | | - Robert Brown
- Department of Pathology and Laboratory Medicine, UT Health, University of Texas Health Science Center, Houston, Texas
| | - Mary McGuire
- Department of Pathology and Laboratory Medicine, UT Health, University of Texas Health Science Center, Houston, Texas
| | - Siquing Fu
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Sarina Piha-Paul
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Aung Naing
- Department of Investigational Cancer Therapeutics, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anthony P Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Robert S Benjamin
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Indreshpal Kaur
- Cell Therapy Labs, GMP Laboratory, Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | |
Collapse
|
|
30
|
Anagnostou V, Yarchoan M, Hansen AR, Wang H, Verde F, Sharon E, Collyar D, Chow LQM, Forde PM. Immuno-oncology Trial Endpoints: Capturing Clinically Meaningful Activity. Clin Cancer Res 2018; 23:4959-4969. [PMID: 28864724 DOI: 10.1158/1078-0432.ccr-16-3065] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Revised: 06/26/2017] [Accepted: 07/10/2017] [Indexed: 12/11/2022]
Abstract
Immuno-oncology (I-O) has required a shift in the established paradigm of toxicity and response assessment in clinical research. The design and interpretation of cancer clinical trials has been primarily driven by conventional toxicity and efficacy patterns observed with chemotherapy and targeted agents, which are insufficient to fully inform clinical trial design and guide therapeutic decisions in I-O. Responses to immune-targeted agents follow nonlinear dose-response and dose-toxicity kinetics mandating the development of novel response evaluation criteria. Biomarker-driven surrogate endpoints may better capture the mechanism of action and biological response to I-O agents and could be incorporated prospectively in early-phase I-O clinical trials. While overall survival remains the gold standard for evaluation of clinical efficacy of I-O agents in late-phase clinical trials, exploration of potential novel surrogate endpoints such as objective response rate and milestone survival is to be encouraged. Patient-reported outcomes should also be assessed to help redefine endpoints for I-O clinical trials and drive more efficient drug development. This paper discusses endpoints used in I-O trials to date and potential optimal endpoints for future early- and late-phase clinical development of I-O therapies.
Collapse
Affiliation(s)
- Valsamo Anagnostou
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Mark Yarchoan
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Aaron R Hansen
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre-University Health Network, Department of Medicine, University of Toronto, Toronto, Canada
| | - Hao Wang
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Franco Verde
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Elad Sharon
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, Maryland
| | | | | | - Patrick M Forde
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
| |
Collapse
|
|
31
|
Ferrara R, Pilotto S, Caccese M, Grizzi G, Sperduti I, Giannarelli D, Milella M, Besse B, Tortora G, Bria E. Do immune checkpoint inhibitors need new studies methodology? J Thorac Dis 2018; 10:S1564-S1580. [PMID: 29951307 PMCID: PMC5994495 DOI: 10.21037/jtd.2018.01.131] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2018] [Accepted: 01/19/2018] [Indexed: 12/26/2022]
Abstract
Immune checkpoint inhibitors (ICI) have widely reshaped the treatment paradigm of advanced cancer patients. Although multiple studies are currently evaluating these drugs as monotherapies or in combination, the choice of the most accurate statistical methods, endpoints and clinical trial designs to estimate the benefit of ICI remains an unsolved methodological issue. Considering the unconventional patterns of response or progression [i.e., pseudoprogression, hyperprogression (HPD)] observed with ICI, the application in clinical trials of novel response assessment tools (i.e., iRECIST) able to capture delayed benefit of immunotherapies and/or to quantify tumor dynamics and kinetics over time is an unmet clinical need. In addition, the proportional hazard model and the conventional measures of survival [i.e., median overall or progression free survival (PFS) and hazard ratios (HR)] might usually result inadequate in the estimation of the long-term benefit observed with ICI. For this reason, innovative methodologies such as milestone analysis, restricted mean survival time (RMST), parametric models (i.e., Weibull distribution, weighted log rank test), should be systematically investigated in clinical trials in order to adequately quantify the fraction of patients who are "cured", represented by the tails of the survival curves. Regarding predictive biomarkers, in particular PD-L1 expression, the integration and harmonization of the existing assays are urgently needed to provide clinicians with reliable diagnostic tests and to improve patient selection for immunotherapy. Finally, developing original and high-quality study designs, such as adaptive or basket biomarker enriched clinical trials, included in large collaborative platforms with multiple active sites and cross-sector collaboration, represents the successful strategy to optimally assess the benefit of ICI in the next future.
Collapse
Affiliation(s)
- Roberto Ferrara
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Sara Pilotto
- U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Mario Caccese
- U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Giulia Grizzi
- U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | | | | | | | - Benjamin Besse
- Department of Medical Oncology, Gustave Roussy, Villejuif, France
| | - Giampaolo Tortora
- U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| | - Emilio Bria
- U.O.C. Oncology, University of Verona, Comprehensive Cancer Center, Azienda Ospedaliera Universitaria Integrata, Verona, Italy
| |
Collapse
|
|
32
|
Jatoi I, Benson JR, Kunkler I. Hypothesis: can the abscopal effect explain the impact of adjuvant radiotherapy on breast cancer mortality? NPJ Breast Cancer 2018; 4:8. [PMID: 29644338 PMCID: PMC5882959 DOI: 10.1038/s41523-018-0061-y] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 03/08/2018] [Accepted: 03/09/2018] [Indexed: 12/19/2022] Open
Abstract
Radiotherapy is an integral component of loco-regional therapy for breast cancer. Randomized controlled trials indicate that increasing the extent of extirpative surgery primarily reduces the risk of local recurrences, while the addition of radiotherapy to surgery can also reduce the risk of distant recurrences, thereby lowering breast cancer-specific mortality. This may suggest an “abscopal” effect beyond the immediate zone of loco-regional irradiation that favorably perturbs the natural history of distant micrometastases. Immunological phenomena such as “immunogenic cell death” provide a plausible mechanistic link between the local and systemic effects of radiation. Radiotherapy treatment can stimulate both pro-immunogenic and immunosuppressive pathways with a potential net beneficial effect on anti-tumor immune activity. Upregulation of programmed cell death ligand (PD-L1) by radiotherapy is an immunosuppressive pathway that could be approached with anti-PD-L1 therapy with potential further improvement in survival. The world overview of randomized trials indicates that the breast cancer mortality reduction from adjuvant radiotherapy is delayed relative to that of adjuvant systemic treatments, and similar delays in the separation of survival curves are evident in the majority of randomized immunotherapy trials demonstrating treatment efficacy. In this article, we hypothesize that an abscopal effect may explain the benefit of radiotherapy in reducing breast cancer mortality, and that It might be possible to harness and augment this effect with systemic agents to reduce the risk of late recurrences.
Collapse
Affiliation(s)
- Ismail Jatoi
- 1Department of Surgery, University of Texas Health Science Center, San Antonio, Texas USA
| | - John R Benson
- 2Cambridge Breast Unit, Addenbrooke's Hospital, Cambridge and Faculty of Medical Sciences, Anglia Ruskin University, Cambridge, UK
| | - Ian Kunkler
- 3Institute of Genetic and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK
| |
Collapse
|
|
33
|
Yue C, Jiang Y, Li P, Wang Y, Xue J, Li N, Li D, Wang R, Dang Y, Hu Z, Yang Y, Xu J. Dynamic change of PD-L1 expression on circulating tumor cells in advanced solid tumor patients undergoing PD-1 blockade therapy. Oncoimmunology 2018; 7:e1438111. [PMID: 29900038 PMCID: PMC5993493 DOI: 10.1080/2162402x.2018.1438111] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2018] [Revised: 02/01/2018] [Accepted: 02/02/2018] [Indexed: 12/26/2022] Open
Abstract
Background: Tumor PD-L1 levels have predictive value in PD-1/PD-L1 checkpoint blockade therapies, yet biopsies can only provide baseline information. Whether PD-L1 expression on circulating tumor cells (CTCs) could serve as an alternative biomarker is of great interest. Design: We established an immunofluorescence assay for semi-quantitative assessment of the PD-L1 expression levels on CTCs with four categories (PD-L1negative, PD-L1low, PD-L1medium and PD-L1high). 35 patients with different advanced gastrointestinal tumors were enrolled in a phase 1 trial of a PD-1 inhibitor, IBI308. The CTC numeration and the PD-L1 expression levels were analyzed. Results: Prior the treatment of IBI308, 97% (34/35) patients had CTCs, ranging from1 to 70 (median 7). 74% (26/35) had PD-L1positive CTCs, and 60% (21/35) had at least one PD-L1high CTCs. The disease control (DC) rate in PD-L1high patients (48%) is much higher than the others (14%). The group with at least 20% abundance of PD-L1high CTCs had even higher DC rate of 64% (9/14), with only 14% DC rate for the rest (3/21). We also observed that the count changes of total CTC, PD-L1postive CTC and PD-L1high CTC correlate quite well with disease outcome (P<0.001, P = 0.002 and 0.007, respectively). In addition, the abundance of PD-L1high CTCs at baseline had predicative significance for progression free survival (PFS). Conclusions: We revealed that the abundance of PD-L1high CTCs at baseline might serve as a predictor to screen patients for PD-1/PD-L1 blockade therapies and measuring the dynamic changes of CTC could indicate the therapeutic response at early time.
Collapse
Affiliation(s)
- Chunyan Yue
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, P. R. China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Yubo Jiang
- Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, P. R. China
| | - Ping Li
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, P. R. China
| | - Yuehua Wang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, P. R. China
| | - Jian Xue
- Nanopep Biotech Co., Beijing, P. R. China
| | - Nannan Li
- Nanopep Biotech Co., Beijing, P. R. China
| | - Da Li
- Nanopep Biotech Co., Beijing, P. R. China
| | - Ruina Wang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai China
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Yongjun Dang
- Key Laboratory of Metabolism and Molecular Medicine, the Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai China
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan University, Shanghai, China
| | - Zhiyuan Hu
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, P. R. China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, P. R. China
- Center for Neuroscience Research, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian Province, P. R. China
| | - Yanlian Yang
- CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterial and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing, P. R. China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, P. R. China
| | - Jianming Xu
- Affiliated Hospital Cancer Center, Academy of Military Medical Sciences, P. R. China
| |
Collapse
|
|
34
|
Teulings HE, Tjin EPM, Willemsen KJ, van der Kleij S, ter Meulen S, Kemp EH, Krebbers G, van Noesel CJM, Franken CLMC, Drijfhout JW, Melief CJM, Nieuweboer-Krobotova L, Nieweg OE, van der Hage JA, van der Veen JPW, Relyveld GN, Luiten RM. Anti-Melanoma immunity and local regression of cutaneous metastases in melanoma patients treated with monobenzone and imiquimod; a phase 2 a trial. Oncoimmunology 2018; 7:e1419113. [PMID: 29632737 PMCID: PMC5889200 DOI: 10.1080/2162402x.2017.1419113] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 12/11/2017] [Accepted: 12/12/2017] [Indexed: 11/04/2022] Open
Abstract
Vitiligo development in melanoma patients during immunotherapy is a favorable prognostic sign and indicates breakage of tolerance against melanocytic/melanoma antigens. We investigated a novel immunotherapeutic approach of the skin-depigmenting compound monobenzone synergizing with imiquimod in inducing antimelanoma immunity and melanoma regression. Stage III-IV melanoma patients with non-resectable cutaneous melanoma metastases were treated with monobenzone and imiquimod (MI) therapy applied locally to cutaneous metastases and adjacent skin during 12 weeks, or longer. Twenty-one of 25 enrolled patients were evaluable for clinical assessment at 12 weeks. MI therapy was well-tolerated. Partial regression of cutaneous metastases was observed in 8 patients and stable disease in 1 patient, reaching the statistical endpoint of treatment efficacy. Continued treatment induced clinical response in 11 patients, including complete responses in three patients. Seven patients developed vitiligo-like depigmentation on areas of skin that were not treated with MI therapy, indicating a systemic effect of MI therapy. Melanoma-specific antibody responses were induced in 7 of 17 patients tested and melanoma-specific CD8+T-cell responses in 11 of 15 patients tested. These systemic immune responses were significantly increased during therapy as compared to baseline in responding patients. This study shows that MI therapy induces local and systemic anti-melanoma immunity and local regression of cutaneous metastases in 38% of patients, or 52% during prolonged therapy. This study provides proof-of-concept of MI therapy, a low-cost, broadly applicable and well-tolerated treatment for cutaneous melanoma metastases, attractive for further clinical investigation.
Collapse
Affiliation(s)
- Hansje-Eva Teulings
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Depts. of Dermatology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Esther P. M. Tjin
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Karina J. Willemsen
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Stephanie van der Kleij
- Depts. of Dermatology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Sylvia ter Meulen
- Surgical Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - E. Helen Kemp
- Dept. of Oncology and Metabolism, University of Sheffield, Sheffield, UK
| | - Gabrielle Krebbers
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Carel J. M. van Noesel
- Dept. of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| | - Cornelis L. M. C. Franken
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | - Jan W. Drijfhout
- Dept. of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands
| | | | - Ludmila Nieuweboer-Krobotova
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Depts. of Dermatology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Omgo E. Nieweg
- Surgical Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jos A. van der Hage
- Surgical Oncology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - J. P. Wietze van der Veen
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
- Depts. of Dermatology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Germaine N. Relyveld
- Depts. of Dermatology, Antoni van Leeuwenhoek Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Rosalie M. Luiten
- Dept. of Dermatology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
| |
Collapse
|
|
35
|
Calpe-Armero P, Ferriols-Lisart R, Ferriols-Lisart F, Pérez-Pitarch A. Effectiveness of Nivolumab versus Docetaxel as Second-Line Treatment in Non-Small Cell Lung Cancer Patients in Clinical Practice. Chemotherapy 2017; 62:374-380. [PMID: 29045938 DOI: 10.1159/000475803] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2017] [Accepted: 04/12/2017] [Indexed: 11/19/2022]
Abstract
AIMS To evaluate the effectiveness of nivolumab as second-line treatment compared to standard therapy with docetaxel in adult patients with non-small cell lung cancer (NSCLC) in clinical practice. METHODS This is an observational, retrospective cohort study of adult patients diagnosed with NSCLC, stage III-IV, treated with docetaxel or nivolumab as second-line treatment. The end points evaluated were overall survival (OS) and progression-free survival (PFS). PFS and OS were described using the Kaplan-Meier method. The Cox proportional hazards model was applied to identify independent prognostic and predictive factors related to disease progression or death. RESULTS Thirty-three patients were included in this study (i.e., 14 in the nivolumab group and 19 in the docetaxel group). Nonsquamous NSCLC was the most frequent histological subtype. Cohorts were homogeneous. The follow-up time was 116 ± 87.3 days. The median PFS was 84 days (95% CI 39-300) for patients treated with nivolumab and 61 days (95% CI 48-76) for patients treated with docetaxel. The risk of progression was 60% lower for patients treated with nivolumab (HR 0.40; 95% CI 0.16-0.97; p = 0.043) compared to patients receiving docetaxel. Among the patients treated with docetaxel, the median OS was 129 days (95% CI 106-300). More than 50% of the patients treated with nivolumab were alive at the end of the follow-up period; nevertheless, the risk difference was not statistically significant (HR 0.55; 95% CI 0.20-1.51; p = 0.244). CONCLUSION NSCLC patients treated with nivolumab as second-line therapy had a longer PFS compared to patients treated with docetaxel in a health care environment.
Collapse
Affiliation(s)
- Pablo Calpe-Armero
- Pharmacy Department, University Clinical Hospital of Valencia, Valencia, Spain
| | | | | | | |
Collapse
|
|
36
|
Kumar C, Kohli S, Chiliveru S, Jain M, Sharan B. Complete remission of rare adenocarcinoma of the oropharynx with APCEDEN ® (dendritic cell-based vaccine): a case report. Clin Case Rep 2017; 5:1692-1696. [PMID: 29026574 PMCID: PMC5628247 DOI: 10.1002/ccr3.1169] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Revised: 07/24/2017] [Accepted: 08/07/2017] [Indexed: 01/09/2023] Open
Abstract
APCEDEN® is an autologous monocyte‐derived dendritic cell‐based immunotherapy. A 58‐year‐old man with adenocarcinoma of oropharynx shows complete remission after receiving APCEDEN® in conjunction with Geftinib validated by reduction in size, whereas Gefitinib alone lead to disease progression.
Collapse
Affiliation(s)
| | | | | | - Minish Jain
- Medical Oncology Ruby Hall Clinic Pune India
| | | |
Collapse
|
|
37
|
Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control. Radiother Oncol 2017; 125:80-88. [PMID: 28916225 DOI: 10.1016/j.radonc.2017.08.009] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Revised: 07/19/2017] [Accepted: 08/05/2017] [Indexed: 01/20/2023]
Abstract
BACKGROUND Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). RESULTS The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). CONCLUSIONS In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.
Collapse
|
|
38
|
Kumar C, Kohli S, Chiliveru S, Bapsy PP, Jain M, Suresh Attili VS, Mohan J, Vaid AK, Sharan B. A retrospective analysis comparing APCEDEN ® dendritic cell immunotherapy with best supportive care in refractory cancer. Immunotherapy 2017; 9:889-897. [PMID: 28838282 DOI: 10.2217/imt-2017-0064] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM A retrospective survival benefit analysis of APCEDEN®, APAC BIOTECH Pvt Ltd 69, Jacranda Marg, DLF PHASE II, Gurugram, Haryana, India, an autologous dendritic cell-based product for management of refractory solid malignancies, was performed in comparison with a control group. METHODS Subjects (retrospective data) whose survival data, geographical region, age, gender, ECOG performance status and stage of disease that could be matched with the treatment group were considered for analysis. RESULTS The analysis suggests a significant survival benefit of 199 days for the APCEDEN therapy treatment group when compared with the control group (356 vs 157 days). The event-free survival time of APCEDEN therapy was 439 days in patients who demonstrated an objective response at first evaluation as per immune-related response criteria. CONCLUSION APCEDEN demonstrated highly convincing survival benefits when compared with the control group.
Collapse
Affiliation(s)
| | | | | | | | - Minish Jain
- Medical Onoclogy, Ruby Hall Clinic, Pune, India
| | | | - Jagan Mohan
- Clinsync Clinical Research Pvt Ltd, Hyderabad, India
| | - Ashok K Vaid
- Medical Oncology & Hematology, Medanta -The Medicity, Gurgaon, India
| | | |
Collapse
|
|
39
|
Abstract
While many decades of scientific research studies have gone into harnessing the power of the immune system to fight cancer, only recently have cancer immunotherapeutic approaches begun to show robust clinical responses in patients with a variety of cancers. These treatments are adding to the current arsenal of cancer treatments; surgery, radiation and chemotherapy, and increasing the therapeutic options for cancer patients. Despite these advances, issues associated with these therapies include that not all patients respond to these therapies, and some patients who respond experience varying degrees of toxicities. One of the major issues affecting immunotherapy is the inability to evaluate trafficking of activated T-cells into sites of tumor. The current diagnostic imaging based on conventional anatomic imaging, which is the mainstay to monitor response to cytotoxic chemotherapy or radiation, is not adequate to assess initial response to immunotherapy or disease evolution. Patients’ prognosis by histological analysis has limited use in regards to immunotherapy. Thus, there is a crucial need for noninvasive biomarkers for screening patients that show long term response to therapy. Here, we provide a brief account of emerging molecular magnetic resonance imaging biomarkers that have potential to exploit the metabolism and metabolic products of activated T cells.
Collapse
|
|
40
|
Wilkie KP, Hahnfeldt P. Modeling the Dichotomy of the Immune Response to Cancer: Cytotoxic Effects and Tumor-Promoting Inflammation. Bull Math Biol 2017; 79:1426-1448. [PMID: 28585066 DOI: 10.1007/s11538-017-0291-4] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2015] [Accepted: 05/04/2017] [Indexed: 12/18/2022]
Abstract
Although the immune response is often regarded as acting to suppress tumor growth, it is now clear that it can be both stimulatory and inhibitory. The interplay between these competing influences has complex implications for tumor development, cancer dormancy, and immunotherapies. In fact, early immunotherapy failures were partly due to a lack in understanding of the nonlinear growth dynamics these competing immune actions may cause. To study this biological phenomenon theoretically, we construct a minimally parameterized framework that incorporates all aspects of the immune response. We combine the effects of all immune cell types, general principles of self-limited logistic growth, and the physical process of inflammation into one quantitative setting. Simulations suggest that while there are pro-tumor or antitumor immunogenic responses characterized by larger or smaller final tumor volumes, respectively, each response involves an initial period where tumor growth is stimulated beyond that of growth without an immune response. The mathematical description is non-identifiable which allows an ensemble of parameter sets to capture inherent biological variability in tumor growth that can significantly alter tumor-immune dynamics and thus treatment success rates. The ability of this model to predict non-intuitive yet clinically observed patterns of immunomodulated tumor growth suggests that it may provide a means to help classify patient response dynamics to aid identification of appropriate treatments exploiting immune response to improve tumor suppression, including the potential attainment of an immune-induced dormant state.
Collapse
Affiliation(s)
- Kathleen P Wilkie
- Center of Cancer Systems Biology, Boston, MA, USA.
- Department of Mathematics, Ryerson University, Toronto, ON, Canada.
| | | |
Collapse
|
|
41
|
Maia MC, Hansen AR. A comprehensive review of immunotherapies in prostate cancer. Crit Rev Oncol Hematol 2017; 113:292-303. [PMID: 28427519 DOI: 10.1016/j.critrevonc.2017.02.026] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 01/21/2023] Open
Abstract
Prostate cancer is the second most common malignant neoplasm in men worldwide and the fifth cause of cancer-related death. Although multiple new agents have been approved for metastatic castration resistant prostate cancer over the last decade, it is still an incurable disease. New strategies to improve cancer control are needed and agents targeting the immune system have shown encouraging results in many tumor types. Despite being attractive for immunotherapies due to the expression of various tumor associated antigens, the microenvironment in prostate cancer is relatively immunosuppressive and may be responsible for the failures of various agents targeting the immune system in this disease. To date, sipuleucel-T is the only immunotherapy that has shown significant clinical efficacy in this setting, although the high cost and potential trial flaws have precluded its widespread incorporation into clinical practice. Issues with patient selection and trial design may have contributed to the multiple failures of immunotherapy in prostate cancer and provides an opportunity to tailor future studies to evaluate these agents more accurately. We have reviewed all the completed immune therapy trials in prostate cancer and highlight important considerations for the next generation of clinical trials.
Collapse
Affiliation(s)
- Manuel Caitano Maia
- Department of Medical Oncology, Instituto do Câncer do Estado de São Paulo (ICESP), Av. Dr Arnaldo, 251, Cerqueira César, CEP 01246-000, São Paulo, Brazil.
| | - Aaron R Hansen
- Department of Medical Oncology and Hematology, Princess Margaret Hospital, 610 University Ave, Toronto, ON, Canada; Department of Medicine, University of Toronto, Medical Sciences Building, 1 King's College Cir#3172, Toronto, ON, Canada
| |
Collapse
|
|
42
|
Keam B, Jung H, Nam BH. Optimal design and endpoint of clinical trials using immune checkpoint blocking agents. Expert Rev Anticancer Ther 2016; 16:1217-1218. [PMID: 27740862 DOI: 10.1080/14737140.2016.1248945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Affiliation(s)
- Bhumsuk Keam
- a Department of Internal Medicine , Seoul National University Hospital , Seoul , Republic of Korea
| | - Hun Jung
- b Merck Sharp & Dohme , Seoul , Republic of Korea
| | - Byung Ho Nam
- c National Cancer Center , Goyang , Republic of Korea
| |
Collapse
|
|
43
|
Rampling R, Peoples S, Mulholland PJ, James A, Al-Salihi O, Twelves CJ, McBain C, Jefferies S, Jackson A, Stewart W, Lindner J, Kutscher S, Hilf N, McGuigan L, Peters J, Hill K, Schoor O, Singh-Jasuja H, Halford SE, Ritchie JWA. A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma. Clin Cancer Res 2016; 22:4776-4785. [PMID: 27225692 PMCID: PMC5026298 DOI: 10.1158/1078-0432.ccr-16-0506] [Citation(s) in RCA: 116] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/11/2016] [Indexed: 12/31/2022]
Abstract
PURPOSE To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue. EXPERIMENTAL DESIGN Patients were HLA-A*02-positive and had undergone tumor resection. Vaccination comprised 11 intradermal injections with IMA950 plus granulocyte macrophage colony-stimulating factor (GM-CSF) over a 24-week period, beginning 7 to 14 days prior to initiation of chemoradiotherapy (Cohort 1) or 7 days after chemoradiotherapy (Cohort 2). Safety was assessed according to NCI CTCAE Version 4.0 and TUMAP-specific T-cell immune responses determined. Secondary observations included progression-free survival (PFS), pretreatment regulatory T cell (Treg) levels, and the effect of steroids on T-cell responses. RESULTS Forty-five patients were recruited. Related adverse events included minor injection site reactions, rash, pruritus, fatigue, neutropenia and single cases of allergic reaction, anemia and anaphylaxis. Two patients experienced grade 3 dose-limiting toxicity of fatigue and anaphylaxis. Of 40 evaluable patients, 36 were TUMAP responders and 20 were multi-TUMAP responders, with no important differences between cohorts. No effect of pretreatment Treg levels on IMA950 immunogenicity was observed, and steroids did not affect TUMAP responses. PFS rates were 74% at 6 months and 31% at 9 months. CONCLUSIONS IMA950 plus GM-CSF was well-tolerated with the primary immunogenicity endpoint of observing multi-TUMAP responses in at least 30% of patients exceeded. Further development of IMA950 is encouraged. Clin Cancer Res; 22(19); 4776-85. ©2016 AACRSee related commentary by Lowenstein and Castro, p. 4760.
Collapse
Affiliation(s)
- Roy Rampling
- University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Sharon Peoples
- Edinburgh Centre for Neuro-Oncology, Western General Hospital, Edinburgh, United Kingdom
| | - Paul J Mulholland
- Department of Oncology, University College London Hospitals, London, United Kingdom
| | - Allan James
- University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom
| | - Omar Al-Salihi
- Adult Neuro-Oncology, Southampton University Hospitals NHS Trust, Southampton, United Kingdom
| | - Christopher J Twelves
- Cancer Research UK Clinical Centre, St James's University Hospital, Leeds, United Kingdom
| | - Catherine McBain
- The Christie NHS Foundation Trust, Withington, Manchester, United Kingdom
| | - Sarah Jefferies
- Cambridge Cancer Trials Centre, Oncology Clinical Trials, Addensbrooke's Hospital, Cambridge, United Kingdom
| | - Alan Jackson
- Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom
| | - Willie Stewart
- Department of Neuropathology, The Queen Elizabeth University Hospital, Glasgow, United Kingdom
| | - Juha Lindner
- Immatics Biotechnologies GmbH, Tübingen, Germany
| | | | - Norbert Hilf
- Immatics Biotechnologies GmbH, Tübingen, Germany
| | - Lesley McGuigan
- Cancer Research UK Centre for Drug Development, London, United Kingdom
| | - Jane Peters
- Cancer Research UK Centre for Drug Development, London, United Kingdom
| | - Karen Hill
- Cancer Research UK Centre for Drug Development, London, United Kingdom
| | | | | | - Sarah E Halford
- Cancer Research UK Centre for Drug Development, London, United Kingdom
| | - James W A Ritchie
- Cancer Research UK Centre for Drug Development, London, United Kingdom.
| |
Collapse
|
|
44
|
Caballero-Baños M, Benitez-Ribas D, Tabera J, Varea S, Vilana R, Bianchi L, Ayuso JR, Pagés M, Carrera G, Cuatrecasas M, Martin-Richard M, Cid J, Lozano M, Castells A, García-Albéniz X, Maurel J, Vilella R. Phase II randomised trial of autologous tumour lysate dendritic cell plus best supportive care compared with best supportive care in pre-treated advanced colorectal cancer patients. Eur J Cancer 2016; 64:167-74. [DOI: 10.1016/j.ejca.2016.06.008] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 05/24/2016] [Accepted: 06/07/2016] [Indexed: 12/29/2022]
|
|
45
|
Monitoring PD-L1 positive circulating tumor cells in non-small cell lung cancer patients treated with the PD-1 inhibitor Nivolumab. Sci Rep 2016; 6:31726. [PMID: 27553175 PMCID: PMC4995431 DOI: 10.1038/srep31726] [Citation(s) in RCA: 227] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 07/25/2016] [Indexed: 11/08/2022] Open
Abstract
Controversial results on the predictive value of programmed death ligand 1 (PD-L1) status in lung tumor tissue for response to immune checkpoint inhibitors do not allow for any conclusive consideration. Liquid biopsy might allow real-time sampling of patients for PD-L1 through the course of the disease. Twenty-four stage IV NSCLC patients included in the Expanded Access Program with Nivolumab were enrolled. Circulating tumor cells (CTCs) were analyzed by CellSearch with anti-human B7-H1/PD-L1 PE-conjugated antibody. PD-L1 expressing CTCs were assessed at baseline, at 3 and 6 months after starting therapy, and correlated with outcome. At baseline and at 3 months of treatment, the presence of CTCs and the expression of PD-L1 on their surface were found associated to poor patients outcome. Nevertheless, the high frequency of PD-L1 expressing CTCs hampered to discriminate the role of PD-L1 in defining prognosis. Conversely although CTCs were found in all patients 6 months after treatment, at this time patients could be dichotomized into two groups based PD-L1 expression on CTCs. Patients with PD-L1 negative CTCs all obtained a clinical benefit, while patients with PD-L1 (+) CTCs all experienced progressive disease. This suggests that the persistence of PD-L1(+) CTCs might mirror a mechanism of therapy escape.
Collapse
|
|
46
|
Decatris MP, O'Byrne KJ. Immune checkpoint inhibitors as first-line and salvage therapy for advanced non-small-cell lung cancer. Future Oncol 2016; 12:1805-22. [DOI: 10.2217/fon-2016-0086] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Advanced non-small-cell lung cancer (NSCLC) has a poor prognosis with few treatment options available for patients after failure of first-line therapy. Nivolumab is the first immune checkpoint inhibitor targeting the PD-1 to be approved in recurrent NSCLC with squamous and nonsquamous histology. More recently, pembrolizumab has also been approved as salvage therapy in PD-L1-positive recurrent NSCLC. The success of immunotherapy in malignant melanoma, previously a disease with no effective treatment, has generated optimism and expectation that some of the checkpoint inhibitors currently in clinical development will soon become available as first-line therapy and hence improve outcomes for the vast majority of patients with advanced NSCLC. This article summarizes the progress accomplished in the field and discusses controversies surrounding the use of immune checkpoint inhibitors.
Collapse
Affiliation(s)
- Marios P Decatris
- Gloucestershire Oncology Centre, Cheltenham General Hospital, Sandford Road, Cheltenham GL53 7AN, UK
| | - Kenneth J O'Byrne
- Princess Alexandra Hospital & Queensland University of Technology, Brisbane, Queensland 4102, Australia
| |
Collapse
|
|
47
|
|
|
48
|
Harris SJ, Brown J, Lopez J, Yap TA. Immuno-oncology combinations: raising the tail of the survival curve. Cancer Biol Med 2016; 13:171-93. [PMID: 27458526 PMCID: PMC4944548 DOI: 10.20892/j.issn.2095-3941.2016.0015] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 03/11/2016] [Indexed: 12/13/2022] Open
Abstract
There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer, immune checkpoint inhibitors also appear to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.
Collapse
Affiliation(s)
| | | | | | - Timothy A. Yap
- Drug Development Unit
- Lung Unit, Royal Marsden Hospital and The Institute of Cancer Research, London SM2 5PT, UK
| |
Collapse
|
|
49
|
Drakes ML, Stiff PJ. Understanding dendritic cell immunotherapy in ovarian cancer. Expert Rev Anticancer Ther 2016; 16:643-52. [DOI: 10.1080/14737140.2016.1178576] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
|
|
50
|
Abstract
The classical model for identification and clinical development of anticancer agents was based on small molecules, which were often quite toxic. Early studies in small groups of patients would seek to identify a maximum tolerated dose and major dose-limiting toxicities. Tumor response (shrinkage) would be assessed after a minimum number of doses in phase II testing. The decision to take the drug into the randomized phase III clinical setting was usually based on the proportion and duration of objective tumor responses, along with overall survival compared with historical controls. Immune-oncologics that are designed to fight cancer by direct CD8(+) T-cell priming and activation or by blocking a negative regulatory molecule have a number of sharp distinctions from cytotoxic drugs. These include cytoreductive effects that may be very different in timing of onset from traditional chemotherapy and the potential for inducing long-term durable remissions even in heavily pretreated patients with metastatic disease. In this paper we review the different classes of immune-oncologic drugs in clinical development with particular attention to the biostatistical challenges associated with evaluating efficacy in clinical trials. Confronting these issues upfront is particularly important given the rapidly expanding number of clinical trials with both monotherapy and combination trials in immunooncology.
Collapse
|