Key issues in the development and approval of new anti-cancer immune therapies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15232-e15232
Author(s):  
Al Blunt ◽  
Steve Gyorffy ◽  
Gerald L. Messerschmidt
Keyword(s):  
Clinical Trials ◽  
Objective Response ◽  
Large Data ◽  
Great Promise ◽  
Immune Effector ◽  
Select Group ◽  
Public Data ◽  
Immune Therapies ◽  
The Impact ◽  
Insight Into

e15232 Background: Immunotherapy (IT) is now an established treatment option for a select group of cancer patients, and holds great promise for broader application. However, the number of new IT drug approvals has remained low, despite hundreds of new immune therapies entering clinical trials. Methods: We examined both successes and failures of immune-therapeutics (small molecules, large molecules and cellular therapies) to develop insight into this trend. We searched multiple public data sources including clinicaltrials.gov, PubMed, and other large data bases to identify informative trials and primary endpoints. A key area of our research focus was the rate of objective tumor responses following treatment with the immunotherapy agents. Results: Our main observation was that most clinical trials in solid tumors were characterized by a low rate of objective response. Tumor shrinkage is known to be the final manifestation of a multi-step process that begins with the therapeutic product’s ability to bind to its target, and the subsequent engagement of pathways that result in tumor infiltration and tumor cell destruction. A critical step is a sustained immune effector cell attack on the tumor cells. However, a growing body of evidence supports the concept that both non-cellular and cellular immune therapies are active primarily in the setting of a “very warm” or “hot” tumor microenvironment (TME). We found evidence of a positive correlation between objective responses and the degree of ‘hotness’ of the TME. Importantly, our research indicates that study drugs were typically successful in precisely engaging their targets in the associated pathway. High response appears to require selection of appropriate populations with respect to tissue/organism level pathways that lead to successful tumor destruction. Conclusions: The success of IT drugs requires clinical trial designs based on insight into both the study drug’s target pathway, and the impact of key organism level physiologic processes, (e.g., TME) that interfere with optimal anti-tumor activity. [Table: see text]

scholarly journals Human Genetic Diversity Alters Therapeutic Gene Editing Off-Target Outcomes

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3993-3993
Author(s):  
Linda Yingqi Lin ◽  
Samuele Cancellieri ◽  
Jing Zeng ◽  
Francesco Masillo ◽  
My Anh Nguyen ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Clinical Trials ◽  
Genome Editing ◽  
Gene Editing ◽  
Conflicts Of Interest ◽  
African Ancestry ◽  
Great Promise ◽  
Personal Genome ◽  
Hematopoietic Stem ◽  
The Impact

Abstract CRISPR gene editing holds great promise to modify somatic genomes to ameliorate disease. In silico prediction of homologous sites coupled with biochemical evaluation of possible genomic off-targets may predict genotoxicity risk of individual gene editing reagents. However, standard computational and biochemical methods focus on reference genomes and do not consider the impact of genetic diversity on off-target potential. Here we developed a web application called CRISPRme that explicitly and efficiently integrates human genetic variant datasets with orthogonal genomic annotations to predict and prioritize off-target sites at scale. The method considers both single-nucleotide variants (SNVs) and indels, accounts for bona fide haplotypes, accepts spacer:protospacer mismatches and bulges, and is suitable for personal genome analyses. We tested the tool with a guide RNA (gRNA) targeting the BCL11A erythroid enhancer that has shown therapeutic promise in clinical trials for sickle cell disease (SCD) and β-thalassemia (Frangoul et al. NEJM 2021). We find that the top predicted off-target site is produced by a non-reference allele common in African-ancestry populations (rs114518452, minor allele frequency (MAF) = 4.5%) that introduces a protospacer adjacent motif (PAM) for SpCas9. We validate that SpCas9 generates indels (~9.6% frequency) and chr2 pericentric inversions in a strictly allele-specific manner in edited CD34+ hematopoietic stem/progenitor cells (HSPCs), although a high-fidelity Cas9 variant mitigates this off-target. This report illustrates how population and private genetic variants should be considered as modifiers of genome editing outcomes. We expect that variant-aware off-target assessment will be required for therapeutic genome editing efforts going forward, including both ongoing and future clinical trials, and we provide a powerful approach for comprehensive off-target prediction. CRISPRme is available at crisprme.di.univr.it. Disclosures No relevant conflicts of interest to declare.

scholarly journals Long-term overall survival and prognostic score predicting survival: the IMPACT study in precision medicine

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Apostolia-Maria Tsimberidou ◽  
David S. Hong ◽  
Jennifer J. Wheler ◽  
Gerald S. Falchook ◽  
Filip Janku ◽  
...  
Keyword(s):  
Overall Survival ◽  
Clinical Trials ◽  
Precision Medicine ◽  
Phase 1 ◽  
Prognostic Score ◽  
Objective Response ◽  
Molecular Profiling ◽  
Risk Of Death ◽  
Link Type ◽  
The Impact

Abstract Background In 2007, we initiated IMPACT, a precision medicine program for patients referred for participation in early-phase clinical trials. We assessed the correlation of factors, including genomically matched therapy, with overall survival (OS). Patients and methods We performed molecular profiling (Clinical Laboratory Improvement Amendments) (genes ≤ 182) for patients with lethal/refractory advanced cancers referred to the Phase 1 Clinical Trials Program. Matched therapy, if available, was selected on the basis of genomics. Clinical trials varied over time and included investigational drugs against various targets (single agents or combinations). Patients were followed up for up to 10 years. Results Of 3487 patients who underwent tumor molecular profiling, 1307 (37.5%) had ≥ 1 alteration and received therapy (matched, 711; unmatched, 596; median age, 57 years; 39% men). Most common tumors were gastrointestinal, gynecologic, breast, melanoma, and lung. Objective response rates were: matched 16.4%, unmatched 5.4% (p < .0001); objective response plus stable disease ≥ 6 months rates were: matched 35.3% and unmatched 20.3%, (p < .001). Respective median progression-free survival: 4.0 and 2.8 months (p < .0001); OS, 9.3 and 7.3 months; 3-year, 15% versus 7%; 10-year, 6% vs. 1% (p < .0001). Independent factors associated with shorter OS (multivariate analysis) were performance status > 1 (p < .001), liver metastases (p < .001), lactate dehydrogenase levels > upper limit of normal (p < .001), PI3K/AKT/mTOR pathway alterations (p < .001), and non-matched therapy (p < .001). The five independent factors predicting shorter OS were used to design a prognostic score. Conclusions Matched targeted therapy was an independent factor predicting longer OS. A score to predict an individual patient’s risk of death is proposed. Trial registration ClinicalTrials.gov, NCT00851032, date of registration February 25, 2009.

Tumor mutational burden (TMB) may be a promising predictive biomarker of response to PD-1/PD-L1 targeting in MSI-H colorectal cancer.

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 43-43 ◽  
Author(s):  
Marwan Fakih ◽  
Jaideep Singh Sandhu ◽  
Ching Ouyang ◽  
Ethan Sokol ◽  
Jeffrey S. Ross ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Objective Response ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Large Data ◽  
Predictive Biomarker ◽  
Continuous Variable ◽  
Data Set ◽  
Cut Point ◽  
The Impact

43 Background: PD-1 targeting with pembrolizumab or nivolumab leads to durable clinical benefits in patients (pts) with microsatellite instability-high (MSI-H) tumors. However, 30-35% of mCRC pts with MSI-H tumors will experience progressive disease (PD) as a best response when treated with anti-PD1 agents, highlighting the need of additional predictive biomarkers. Methods: We performed a retrospective multi-center clinical investigation to evaluate the impact of TMB, age, gender, stage at initial presentation, pattern of metastatic disease, tumor grade, and RAS/RAF status on response to anti-PD1/PD-L1 in MSI-H mCRC. TMB and MSI status were determined by hybrid capture-based next-generation sequencing (Foundation Medicine [FM]). The TMB distribution in MSI-H CRC was estimated from a large data set from FM. Results: 22 eligible MSI-H mCRC pts were identified across 5 cancer centers: 19 pts received pembrolizumab, 1 pt received nivolumab, 1 pt received nivolumab + ipilimumab, and 1 pt received durvalumab + tremelimumab. Among tested variables, TMB (as a continuous variable) showed the strongest association with an objective response (OR; p < 0.001). Also, both univariate and multivariate analyses supported that TMB serves as an independent prognostic variable in predicting progression-free survival (PFS; p < 0.001 and p < 0.01, respectively). Using log-rank statistics, the optimal predictive cut-point for TMB was estimated between 37-41 mutations/Mb to dichotomize pts into TMBhigh and TMBlow groups. All 13 pts (100%) with TMBhigh had an OR, while only 2/9 (22%) pts with TMBlow had an OR and 6/9 had PD. The median PFS for TMBhigh pts has not been reached (no progressors, median follow-up > 18 mos), while the median PFS for TMBlow pts was 2 mos. Amongst 821 MSI-H CRC cases tested at FM, the 25th, 35th, 50th and 75th percentile TMB cutoffs were 33.1, 37.4, 46.1, and 61.8 mutations/Mb, respectively. Our optimal TMB cut-point range suggests that MSI-H mCRC with the lowest 35th percentile of TMB have a low likelihood of benefit from anti-PD1. Conclusions: These TMB findings require validation in prospective trials and may guide the sequencing of PD-1 inhibitor monotherapy in MSI-H mCRC.

scholarly journals Clinical landscape of oncolytic virus research in 2020

2020 ◽  
Vol 8 (2) ◽  
pp. e001486 ◽  
Author(s):  
Nicholas Macedo ◽  
David M Miller ◽  
Rizwan Haq ◽  
Howard L Kaufman
Keyword(s):  
Clinical Trials ◽  
Immune Responses ◽  
Plaque Assay ◽  
Cancer Therapeutics ◽  
Oncolytic Viruses ◽  
Low Grade ◽  
Current Profile ◽  
Tumor Biopsy ◽  
The Impact ◽  
Insight Into

Oncolytic viruses (OVs) are a new class of cancer therapeutics. This review was undertaken to provide insight into the current landscape of OV clinical trials. A PubMed search identified 119 papers from 2000 to 2020 with 97 studies reporting data on 3233 patients. The viruses used, presence of genetic modifications and/or transgene expression, cancer types targeted, inclusion of combination strategies and safety profile were reported. In addition, information on viral bioshedding across the studies, including which tissues or body fluids were evaluated and how virus was detected (eg, PCR, plaque assay or both), is also reported. Finally, the number of studies evaluating antiviral and antitumor humoral and cellular immune responses were noted. We found that adenovirus (n=30) is the most common OV in clinical trials with approximately two-thirds (n=63) using modified or recombinant viral backbones and granulocyte-macrophage colony-stimulating factor (n=24) was the most common transgene. The most common tumors targeted were melanoma (n=1000) and gastrointestinal (GI; n=577) cancers with most using monotherapy OVs given by intratumoral (n=1482) or intravenous (n=1347) delivery. The most common combination included chemotherapy (n=36). Overall, OV treatment-related adverse events were low-grade constitutional and local injection site reactions. Viral shedding was frequently measured although many studies restricted this to blood and tumor tissue and used PCR only. While most studies did report antiviral antibody titers (n=63), only a minority of studies reported viral-specific T cell responses (n=10). Tumor immunity was reported in 48 studies and largely relied on general measures of immune activation (eg, tumor biopsy immunohistochemistry (n=25) and serum cytokine measurement (n=19)) with few evaluating tumor-specific immune responses (n=7). Objective responses were reported in 292 (9%) patients and disease control was achieved in 681 (21.1%) patients, although standard reporting criteria were only used in 53% of the trials. Completed clinical trials not reported in the peer-reviewed literature were not included in this review potentially underestimating the impact of OV treatment. These data provide insight into the current profile of OV clinical trials reporting and identifies potential gaps where further studies are needed to better define the role of OVs, alone and in combination, for patients with cancer.

scholarly journals Engineering Strategies to Enhance TCR-Based Adoptive T Cell Therapy

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1485 ◽  
Author(s):  
Jan A. Rath ◽  
Caroline Arber
Keyword(s):  
T Cell ◽  
Cell Receptor ◽  
Clinical Results ◽  
Adoptive T Cell Therapy ◽  
Great Promise ◽  
T Cell Therapy ◽  
Cell Therapies ◽  
Challenges And Opportunities ◽  
The Impact ◽  
Insight Into

T cell receptor (TCR)-based adoptive T cell therapies (ACT) hold great promise for the treatment of cancer, as TCRs can cover a broad range of target antigens. Here we summarize basic, translational and clinical results that provide insight into the challenges and opportunities of TCR-based ACT. We review the characteristics of target antigens and conventional αβ-TCRs, and provide a summary of published clinical trials with TCR-transgenic T cell therapies. We discuss how synthetic biology and innovative engineering strategies are poised to provide solutions for overcoming current limitations, that include functional avidity, MHC restriction, and most importantly, the tumor microenvironment. We also highlight the impact of precision genome editing on the next iteration of TCR-transgenic T cell therapies, and the discovery of novel immune engineering targets. We are convinced that some of these innovations will enable the field to move TCR gene therapy to the next level.

The impact of NCI-sponsored network group clinical trials on guideline care and new drug indications.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 6604-6604
Author(s):  
Joseph M. Unger ◽  
Van T. Nghiem ◽  
Dawn L. Hershman ◽  
Riha Vaidya ◽  
Michael Leo LeBlanc ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Clinical Trials ◽  
Clinical Guidelines ◽  
Research Network ◽  
Phase Iii ◽  
Cancer Clinical Trials ◽  
New Drug ◽  
Public Data ◽  
Drug Approvals ◽  
The Impact

6604 Background: National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying new antineoplastic regimens. However, the clinical impact of their trials has not been systematically examined. We analyzed the influence of network group cancer clinical trials on clinical guidelines and new drug approvals. Methods: We evaluated Phase III cancer clinical trials which the SWOG Cancer Research Network coordinated or participated in (1980-2017). Included trials were completed and its results published. A documented practice influential (DPI) trial was one with verified influence on National Comprehensive Cancer Network (NCCN) clinical guidelines (available starting in 1996) or on U.S. Food and Drug Administration (FDA)-approved package inserts. We estimated the rate of DPI trials overall and over time. The total federal investment supporting the set of trials was also determined based on public data. Results: In total, 182 trials comprising 148,028 patients were studied. We identified 79 DPI studies (43.4%); 73 influenced NCCN guidelines, 12 influenced new drug approvals, and 6 influenced both. The rate of DPI trials was 72.3% (47/65) among formally positive trials (i.e., achieved their protocol specified endpoint) and 27.4% (32/117) among negative trials. Thus 40.5% (32/79) of DPI trials were based on negative studies, half of which (16/32 = 50.0%) reaffirmed standard of care over experimental therapy. There were no differences between DPI and non-DPI trials in key study design characteristics. Total federal investment for the programs conducting the trials was $1.36 billion (USD2017), a rate of $7.5 million per trial, or $17.2 million per DPI trial. Conclusions: Nearly half of all phase III trials by one of the NCTN’s largest groups had documented practice influence on clinical care guidelines or new drug approvals. Even many negative trials impacted guideline recommendations. Compared to the costs of a new drug approval in pharmaceutical companies – typically estimated at > $1 billion – the amount invested by federal funders to provide this valuable evidence was modest. These findings highlight the major role of the NCTN’s clinical trial program in advancing oncology practice.

scholarly journals What is the impact of patient recruitment on offshoring of clinical trials?

2020 ◽  
Vol 16 (1) ◽  
Author(s):  
Maryam Kermanimojarad
Keyword(s):  
Clinical Trials ◽  
Human Subjects ◽  
Policy Decision ◽  
The United States ◽  
Decision Makers ◽  
Related Factors ◽  
Main Driver ◽  
Key Driver ◽  
The Impact ◽  
Insight Into

Abstract The issue of globalization of research is receiving considerable attention due to the increasing number of offshored R&D activities from the United States, Europe, and Japan. This paper explores this phenomenon and provides a model to analyze the factors that will likely contribute to a global transformation of clinical trials. By identifying the main characteristics of clinical trials, I aim to clarify the main driver of the relocation process of clinical research. I reviewed the relevant published articles to address the research questions. The results of this study challenge the traditional thinking of cost-related factors as the major reason for offshoring cilinical trials and show the importance of the recruitment of human subjects in trials. Consequently, this paper suggests that “recruitment crisis” in home country as the main contribution and a key driver to offshore R&D activities, has been underestimated by previous studies. In particular, this study provides policy-decision makers with a new insight into the development issue surrounding the pharmaceutical industry.

A phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3158-TPS3158 ◽  
Author(s):  
Ecaterina Elena Ileana Dumbrava ◽  
Maria E. Suarez-Almazor ◽  
Jeane Painter ◽  
Tanner Johanns ◽  
Michael L. Dougan ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Autoimmune Disease ◽  
Tumor Tissue ◽  
Objective Response ◽  
Autoimmune Disorders ◽  
Severity Level ◽  
Phase Ib ◽  
Advanced Malignancies ◽  
The Impact ◽  
Disease Specific

TPS3158 Background: Immune checkpoint inhibitors (ICI) such as anti-PD-1/PD-L1 antibodies have become a pivotal approach to cancer therapy. Nivolumab is an anti-PD1 antibody approved for an increasing number of solid tumors and hematological malignancies. However, patients (pts) with history of autoimmune disorders are excluded from the majority of clinical trials testing ICI. Consequently, the risks of flares and worsening of pre-existing autoimmune disorders in pts with tumor types who otherwise stand to benefit from ICI therapy are largely unknown, posing a challenge for oncologists. We are conducting a phase Ib study to test the hypothesis that nivolumab can be safely administered to pts with varying severity of Dermatomyositis, Systemic Sclerosis, Rheumatoid Arthritis, Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Multiple Sclerosis, Sjögren's Syndrome and Other Autoimmune Disorders (AIM-Nivo). Methods: AIM-Nivo is an open-label, multi-center ongoing phase Ib study with nivolumab 480mg IV every 28 days in pts with autoimmune diseases and advanced malignancies (NCT03816345). The study has autoimmune disease-specific cohorts overseen by a multidisciplinary group of experts. The primary objective is to assess the overall safety and toxicity profile of nivolumab in pts with autoimmune disorders and advanced malignancies. Secondary objectives are to evaluate the antitumor efficacy, the impact of nivolumab on the autoimmune disease severity indices, and to explore potential biomarkers of response, resistance or toxicity. Key overall inclusion criteria include age ≥18 years, histologically confirmed advanced malignancies in which ICI are approved or have shown clinical activity. Key overall exclusion criteria include prior therapy with anti-PD-1/PD-L1 antibodies. Specific eligibility criteria are defined for each disease-specific cohort. For each autoimmune disorder, severity level of the disease as defined by disease-specific severity indices will be assessed, and up to a total of 12 pts will be included in each disease cohort at each severity level. Primary endpoints are dose-limiting toxicities, adverse events (AEs) and serious AEs. Continuous monitoring of toxicity will be conducted. Key secondary endpoints are best objective response, progression free and overall survival and cohort specific tumor tissue, blood and non-tumor tissue-based biomarkers. The AIM-Nivo trial opened in May 2019 and is enrolling pts through the National Cancer Institute Experimental Therapeutics Clinical Trials Network (ETCTN). Clinical trial information: NCT03816345 .

Crizotinib Versus Chemotherapy on ALK-positive NSCLC: A Systematic Review of Efficacy and Safety

2018 ◽  
Vol 19 (1) ◽  
pp. 41-49 ◽  
Author(s):  
Mingxia Wang ◽  
Guanqi Wang ◽  
Haiyan Ma ◽  
Baoen Shan
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Adverse Events ◽  
Objective Response Rate ◽  
Retrospective Studies ◽  
Response Rate ◽  
Objective Response ◽  
Treated Group ◽  
Efficacy And Safety ◽  
Alk Positive

Introduction: Crizotinib was approved to treat anaplastic lymphoma kinase (ALK)- positive non-small cell lung cancer (NSCLC) by the Food and Drug Administration in 2011.We conducted a systematic review of clinical trials and retrospective studies to compare the efficacy and safety of crizotinib with chemotherapy. </P><P> Methods: We searched electronic databases from inception to Dec. 2016. Clinical trials and retrospective studies regarding crizotinib and crizotinib versus chemotherapy in treatment of NSCLC were eligible. The primary outcomes were the objective response rate (ORR) and disease control rate (DCR). Results: Nine studies (five clinical trials and four retrospective studies) including 729 patients met the inclusion criteria. Crizotinib treatment revealed 1-year OS of 77.1% and PFS of 9.17 months. And crizotinib had a better performance than chemotherapy in ORR (OR: 4.97, 95%CI: 3.16 to 7.83, P<0.00001, I2=35%). DCR revealed superiority with crizotinib than chemotherapy (OR: 3.42, 95% CI: 2.33 to 5.01, P<0.00001, I2=0%). PR (partial response) were significant superior to that of chemotherapy through direct systematic review. No statistically significant difference in CR (complete response) was found between crizotinib-treated group and chemotherapy-treated group. Regarding SD (stable disease), chemotherapy-treated group had a better performance than crizotinib-treated group. Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, nausea, and hematologic toxicity. This systematic review revealed improved objective response rate and increased disease control rate in crizotinib group comparing with chemotherapy group. Crizotinib treatment would be a favorable treatment option for patients with ALK-positive NSCLC. ALK inhibitors may have future potential applications in other cancers driven by ALK or c-MET gene mutations.

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