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.

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.

scholarly journals Predictive biomarkers of response for PD-1/PD-L1 inhibitors: a cumbersome gold rush

2017 ◽  
Vol 5 (3) ◽  
pp. 14-19
Author(s):  
Andrea Vingiani ◽  
Massimo Barberis ◽  
Elena Guerini-Rocco
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Tumor Infiltrating Lymphocytes ◽  
Gold Rush ◽  
Repair Deficiency ◽  
Tumor Mutational Burden ◽  
Predictive Role

Programmed cell death protein 1 (PD-1) and its ligand programmed cell death-ligand 1 (PD-L1) are overexpressed in a number of human malignancies. More interestingly, their expression has been associated with patient survival in non-small cell lung cancer (NSCLC), melanoma, renal cell carcinoma, esophageal, pancreatic and colorectal carcinoma, with the data commonly suggesting a negative prognostic role. In this review, we summarize the pros and cons regarding the predictive role of PD-L1 expression in candidate patients for checkpoint inhibitors. Furthermore, we discuss the potential predictive role of other biomarkers, such as tumor mutational burden, microsatellite instability, mismatch repair deficiency and tumor infiltrating lymphocytes. We conclude that PD-L1 testing probably represents simply a “snapshot” of an intricate, fluctuating and dynamic process, that in turn represents the interplay between the immune system and cancer. The PD-L1 assay can be considered more useful for response stratification than in patient selection.

A landscape analysis of immunotherapy-related biomarkers across solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14268-e14268
Author(s):  
Lara Ann Kujtan ◽  
Scott Morris ◽  
Ashiq Masood ◽  
Janakiraman Subramanian
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitor ◽  
Predictive Biomarkers ◽  
Breast Cancers ◽  
High Demand ◽  
Lung Cancers ◽  
Mutational Burden ◽  
Tumor Mutational Burden ◽  
Tumor Types ◽  
Endometrial Carcinomas

e14268 Background: Checkpoint inhibitor-based immunotherapy has varying success among tumor types and patients. Predictive biomarkers are in high demand to assist with patient selection. Responses to these agents are correlated with programmed cell death ligand 1 (PD-L1) expression, microsatellite instability (MSI), and tumor mutational burden (TMB). Here we evaluated PD-L1 expression, MSI status and TMB in a variety of solid tumors to determine their relationships. Methods: A total of 109 specimens were identified in patients diagnosed with solid tumors that underwent a Paradigm Diagnostic Cancer Test. MSI scores were determined by the number of indels present in runs of 6 homopolymer bases per megabase, with a cut-off of 6 to distinguish between MSI-high (MSI-H) and MSI-stable (MSI-S). TMB scores greater than or equal to 10 muts/Mb were designated as high (TMB-H). Results: Of all tumors, 19.3% were MSI-high. PD-L1 testing was performed in 71.5% of all samples; of these, 21.8% were PD-L1 positive. TMB scores of PD-L1 positive tumors (mean = 10.3 muts/Mb) and PD-L1 negative tumors (mean = 8.6 muts/Mb) did not differ significantly (p = 0.57). All MSI-H tumors were TMB-H, and MSI-H tumors had higher mean TMB scores than MSI-S tumors (57 muts/Mb versus 7.6 muts/Mb; p = 0.06). Among TMB-H tumors, MSI-H status was associated with higher TMB scores compared to MSI-S tumors (55.2 muts/Mb versus 22.1 muts/Mb, p = 0.18). Of the both MSI-S and TMB-H tumors, 68.8% were lung cancers and 18.8% were breast cancers. Tumors both MSI-H and TMB-H were 47.6% gastrointestinal carcinomas and 33.3% endometrial carcinomas. Conclusions: In our analysis, TMB was independent of PD-L1 status. All MSI-H tumors were also TMB-H; these were primarily gastrointestinal and endometrial carcinomas whereas TMB-H tumors that were MSI-S consisted predominantly of lung cancers. This difference may be due to the different mechanisms of acquiring mutations during carcinogenesis in these two tumor types. These data also highlight the need for integrated PD-L1, MSI and TMB testing to identify potential responders to immunotherapy.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

scholarly journals Predicting Responses to Checkpoint Inhibitors in Lymphoma: Are We Up to the Standards of Solid Tumors?

2020 ◽  
Vol 14 ◽  
pp. 117955492097636
Author(s):  
Ah-Reum Jeong ◽  
Edward D Ball ◽  
Aaron Michael Goodman
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
B Cell ◽  
Solid Tumors ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
B Cell Lymphoma ◽  
Hematologic Malignancies ◽  
Checkpoint Blockade ◽  
Programmed Cell Death 1

Treatment of cancer has transformed with the introduction of checkpoint inhibitors. However, the majority of solid tumor patients do not respond to checkpoint blockade. In contrast, the response rate to programmed cell death 1 (PD-1) blockade in relapsed/refractory classical Hodgkin lymphoma (cHL) is 65% to 84% which is the highest among all cancers. Currently, checkpoint inhibitors are only approved for cHL and primary mediastinal B-cell lymphoma as the responses to single-agent checkpoint blockade in other hematologic malignancies is disappointingly low. Various established biomarkers such as programmed cell death 1 ligand 1 (PD-L1) protein surface expression, mismatch repair (MMR) status, and tumor mutational burden (TMB) are routinely used in clinical decision-making in solid tumors. In this review, we will explore these biomarkers in the context of hematologic malignancies. We review characteristic 9p24.1 structural alteration in cHL and primary mediastinal B-cell lymphoma (PMBCL) as a basis for response to PD-1 inhibition, as well as the role of antigen presentation pathways. We also explore the reported frequencies of MMR deficiency in various hematologic malignancies and investigate TMB as a predictive marker.

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