Immunotherapy in combination with PARP inhibition in advanced cervical cancer patients functionally competent or deficient for the Fanconi anemia repair pathway.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS5597-TPS5597
Author(s):  
John Paul Diaz ◽  
Wenrui Duan ◽  
Eric Schroeder ◽  
Zuanel Diaz ◽  
Nicholas Lambrou ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Dna Repair ◽  
Programmed Cell Death ◽  
Phase Ii ◽  
Fanconi Anemia ◽  
Objective Response ◽  
Repair Pathway ◽  
Mutational Burden ◽  
Tumor Mutational Burden

TPS5597 Background: Immunotherapy has improved outcomes for patients with recurrent or metastatic cervical cancer whose tumors express PD-L1. Pembrolizumab (PEM), a monoclonal antibody that binds to programmed cell death 1 (PD 1) receptor, inhibits interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). It is approved for the treatment of recurrent or metastatic cervical cancer. Despite promising results, new strategies are being developed to improve immunotherapy responses. This includes DNA-damaging agents that have the potential to enhance the response to immunotherapy by promoting neo-antigen release, increasing tumor mutational burden, and enhancing PD-L1 expression. Poly-ADP-ribose polymerase (PARP) inhibitors, such as olaparib, have shown synergy with immunotherapy in preclinical and early clinical studies. PARP-based therapy is based on the inhibition of single-strand DNA repair, leading to DNA damage and increased tumor mutational burden. As a result, the tumor becomes a more attractive target for immunotherapy. Based on this, we are investigating the interplay between homologous recombination (HR) repair deficiency, another mechanism of DNA repair, and solid tumor response to ICI. Our approach uses an all-inclusive functional immunofluorescence assay of the Fanconi Anemia triple-staining immunofluorescence (FATSI) we developed and can be performed in paraffin-embedded tumors. Methods: This is a phase II open-label single center trial evaluating the role of PEM and olaparib in patients with metastatic cervical cancer who have progressed on first-line standard of care chemotherapy. FATSI will be performed in all patients. We hypothesize that FATSI negative tumors will be associated with improved responses. Other eligibility criteria include measurable disease by imaging, 18 years of age or older, and no previous exposure to ICI or PARP inhibitor. The primary objective is to evaluate the immune-related objective response rate (iORR) achieved in patients with FA Repair Pathway functionally competent and functionally deficient tumors. Secondary objectives include 20-week progression free survival and overall survival. Other exploratory objectives include evaluation of the mutation load and markers of neo-antigenicity, T cell receptor clonotype analyses (before and after treatment), and alterations in HR repair genes. We will utilize a two-stage phase II design to detect an iORR ≥ 20% in the whole population tested vs. the null hypothesis that the true iORR ≤5%, represents a response by chance alone or other infrequent unknown mechanisms. An interim analysis requires at least 2 of the first 20 evaluable patients enrolled have an objective response. If this occurs, we will accrue 28 additional patients to total 48. Enrollment is ongoing and two patients are currently on treatment. Clinical trial information: NCT04483544.

A metastatic intrahepatic cholangiocarcinoma treated with programmed cell death 1 inhibitor: a case report and literature review

Immunotherapy ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 555-561 ◽  
Author(s):  
Jingjing Zhang ◽  
Lihua Wu ◽  
Jian Liu ◽  
Meihua Lin
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Intrahepatic Cholangiocarcinoma ◽  
Clinical Effectiveness ◽  
First Line ◽  
Mutational Burden ◽  
Programmed Death ◽  
Promising Therapeutic Approach ◽  
Programmed Cell Death 1 ◽  
Tumor Mutational Burden

Intrahepatic cholangiocarcinoma is a disease with grave prognosis due to limited therapeutic regimens. Programmed cell death 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor have shown dramatic clinical effectiveness in multiple solid tumors. Here, we report the case that a patient with metastasis intrahepatic cholangiocarcinoma, being failure of first-line chemotherapy, was enrolled into the Phase I study of a PD-1 inhibitor, sintilimab. The patient achieved complete remission after three cycles of treatment with mild adverse reaction. In addition, the tumor mutational burden and the microsatellite instability status were low in the present case. Hence, PD-1 inhibitor might be a promising therapeutic approach for patients with advanced cholangiocarcinoma.

Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4086-4086 ◽  
Author(s):  
Apurva Jain ◽  
Rachna T. Shroff ◽  
Mingxin Zuo ◽  
Jacqueline Weatherly ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Dna Repair ◽  
Biliary Tract ◽  
Checkpoint Inhibitors ◽  
Repair Pathway ◽  
Biliary Tract Cancers ◽  
Mutational Burden ◽  
Study Results ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

scholarly journals What is the burden of proof for tumor mutational burden in gliomas?

2020 ◽  
Author(s):  
Mustafa Khasraw ◽  
Kyle M Walsh ◽  
Amy B Heimberger ◽  
David M Ashley
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Solid Tumors ◽  
Treatment Options ◽  
Burden Of Proof ◽  
Predictive Biomarkers ◽  
Cns Tumors ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Pan Cancer

Abstract The treatment of patients with a variety of solid tumors has benefitted from immune checkpoint inhibition targeting the anti-programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis. The US Food and Drug Administration (FDA) granted accelerated approval of PD-1 inhibitor, pembrolizumab, for the treatment of adult and pediatric patients with high tumor mutational burden (TMB-H), solid tumors that have progressed following prior treatment, and who have no other treatment options, including the extension to tumors of the central nervous system (CNS). In general, pan-cancer approvals are viewed positively to empower patients and clinicians. There are subsets (eg, BRAF, NTRK) for which this pathway for approval is appropriate. However, the pan-cancer FDA approval of pembrolizumab raises several concerns regarding the generalizability of the evidence to other tumor types, including managing patients with gliomas and other CNS tumors. The cutoff for TMB-H is not well defined. There are intrinsic immunological differences between gliomas and other cancers types, including the immunosuppressive glioma microenvironment, the tumor’s effects on systemic immune function, and the transformation of the T-cell populations to an exhausted phenotype in glioma. Here, we address the caveats with pan-cancer approvals concerning gliomas and complexities of the unique CNS immune environment, discuss potential predictive biomarkers, including TMB, and explain why the recent approval should be applied with caution in CNS tumors.

bTMB-High Basket trial: A multicenter phase II trial of nivolumab monotherapy in patients with advanced gastrointestinal cancers with high blood tumor mutational burden (bTMB).

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. TPS179-TPS179 ◽  
Author(s):  
Yoshiaki Nakamura ◽  
Yoshito Komatsu ◽  
Ken Kato ◽  
Eiji Shinozaki ◽  
Hideaki Bando ◽  
...  
Keyword(s):  
Phase Ii ◽  
Statistical Power ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Multicenter Phase ◽  
Mutational Burden ◽  
Biomarker Analysis ◽  
Tumor Mutational Burden ◽  
Basket Trial ◽  
Disease Specific

TPS179 Background: Tumor mutational burden (TMB) is an emerging biomarker for immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC). Analysis of circulating tumor DNA (ctDNA) has been reported to effectively identify patients likely to respond to ICIs by effectively and non-invasively evaluating the TMB in the tumor in NSCLC and gastric cancer. Methods: We are conducting an investigator-initiated multicenter phase II basket trial to investigate efficacy and safety of nivolumab monotherapy in patients with advanced gastrointestinal (GI) cancers with high bTMB identified by ctDNA analysis as part of the Nationwide Cancer Genome Screening Project (SCRUM-Japan GI-SCREEN). Eligibility criteria include histologically confirmed unresectable or recurrent GI malignancies; ECOG PS of 0 or 1; refractory or intolerant to the standard therapies; and high bTMB identified by a 73-gene sequencing ctDNA panel (Guardant360) regardless of microsatellite instability status. Patients will be enrolled into one of four disease-specific cohorts (colorectal, gastric, esophageal, and other GI cancer cohort), and receive intravenous nivolumab monotherapy of 360 mg every 3 weeks. The bTMB score is calculated by adjustment of mutation count by tumor fraction, and tentative bTMB level cut-offs were determined according to objective response rate (ORR) reported for ICI treatment for each tumor subtype in previous trials. The trial will utilize a two-stage design with a Bayesian hierarchical model, and tentative bTMB level cut-off will be re-assessed in the first stage. Primary endpoint in each stage is the disease control rate at 6 week and the ORR assessed by investigators per RECIST v1.1, respectively. Target sample size is determined as 70 in total so that the statistical power in each disease-specific cohort calculated based on a Bayesian posterior distribution attains 70 to 80% with one-sided alpha level in each cohort of approximately 10%. For biomarker analysis, tumor tissue and ctDNA will be serially collected and analyzed by whole-exome, transcriptome, and T cell receptor sequencing. This trial was initiated since September 2018. Clinical trial information: UMIN000033182.

The role of programmed cell death ligand-1/ programmed cell death-1 (PD-L1/PD-1) in HPV-induced cervical cancer and potential for their use in blockade therapy

2020 ◽  
Vol 27 ◽  
Author(s):  
Lifang Zhang ◽  
Yu Zhao ◽  
Quanmei Tu ◽  
Xiangyang Xue ◽  
Xueqiong Zhu ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Escape ◽  
Hypoxia Inducible Factor ◽  
Hpv Infection ◽  
Advanced Cervical Cancer ◽  
Cervical Carcinogenesis ◽  
Programmed Cell Death 1

Background: Cervical cancer induced by infection with human papillomavirus (HPV) remains a leading cause of mortality for women worldwide although preventive vaccines and early diagnosis have reduced morbidity and mortality. Advanced cervical cancer can only be treated with either chemotherapy or radiotherapy but outcomes are poor. The median survival for advanced cervical cancer patients is only 16.8 months. Methods: We undertook a structural search of peer-reviewed published studies based on 1). Characteristics of programmed cell death ligand-1/programmed cell death-1(PD-L1/PD-1) expression in cervical cancer and upstream regulatory signals of PD-L1/PD-1 expression, 2). The role of the PD-L1/PD-1 axis in cervical carcinogenesis induced by HPV infection and 3). Whether the PD-L1/PD-1 axis has emerged as a potential target for cervical cancer therapies. Results: One hundred and twenty-six published papers were included in the review, demonstrating that expression of PD-L1/PD-1 is associated with HPV-caused cancer, especially with HPV 16 and 18 which account for approximately 70% of cervical cancer cases. HPV E5/E6/E7 oncogenes activate multiple signaling pathways including PI3K/AKT, MAPK, hypoxia-inducible factor 1α, STAT3/NF-kB and MicroRNAs, which regulate PD-L1/PD-1 axis to promote HPV-induced cervical carcinogenesis. The PD-L1/PD-1 axis plays a crucial role in immune escape of cervical cancer through inhibition of host immune response. creating an "immune-privileged" site for initial viral infection and subsequent adaptive immune resistance, which provides a rationale for therapeutic blockade of this axis in HPV-positive cancers. Currently, Phase I/II clinical trials evaluating the effects of PD-L1/PD-1 targeted therapies are in progress for cervical carcinoma, which provide an important opportunity for the application of anti-PD-L1/anti-PD-1 antibodies in cervical cancer treatment. Conclusion: Recent research developments have led to an entirely new class of drugs using antibodies against the PD-L1/PD-1 thus promoting the body’s immune system to fight the cancer. The expression and roles of the PD-L1/ PD-1 axis in the progression of cervical cancer provide great potential for using PD-L1/PD-1 antibodies as a targeted cancer therapy.

Fanconi Anemia DNA Repair Pathway as a New Mechanism to Exploit Cancer Drug Resistance

2020 ◽  
Vol 20 (9) ◽  
pp. 779-787
Author(s):  
Kajal Ghosal ◽  
Christian Agatemor ◽  
Richard I. Han ◽  
Amy T. Ku ◽  
Sabu Thomas ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Dna Repair ◽  
Fanconi Anemia ◽  
Cancer Drug ◽  
Drug Resistant ◽  
Cancer Drugs ◽  
Repair Pathway ◽  
Cancer Drug Resistance ◽  
Anti Cancer ◽  
Cancerous Cells

Chemotherapy employs anti-cancer drugs to stop the growth of cancerous cells, but one common obstacle to the success is the development of chemoresistance, which leads to failure of the previously effective anti-cancer drugs. Resistance arises from different mechanistic pathways, and in this critical review, we focus on the Fanconi Anemia (FA) pathway in chemoresistance. This pathway has yet to be intensively researched by mainstream cancer researchers. This review aims to inspire a new thrust toward the contribution of the FA pathway to drug resistance in cancer. We believe an indepth understanding of this pathway will open new frontiers to effectively treat drug-resistant cancer.

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