The Next Decade of Immune Checkpoint Therapy

Sharma, Padmanee; Siddiqui, Bilal A.; Anandhan, Swetha; Yadav, Shalini S.; Subudhi, Sumit K.; Gao, Jianjun; Goswami, Sangeeta; Allison, James P.

doi:10.1158/2159-8290.cd-20-1680

Cited by 386 publications

(234 citation statements)

References 224 publications

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“…Mouse tumor models C57BL/6AnCrl and BALB/cAnCrl female mice were injected subcutaneously with 2.10 5 TC1, CT26, MC38, B16F10, or B16OVA cells in 100 µL of phosphate buffered saline (PBS 1×, Gibco, France) into the left flank. Tumor growth was monitored every 3 days with a caliper and groups were formed when tumor reached a mean diameter of 50-60 mm 2 . All CT procedures were conducted in the Pharmacy Department of the University Hospital of Besançon (France).…”

Section: Patientsmentioning

confidence: 99%

Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

Joseph

Kirilovsky

Lecoester

et al. 2021

J Immunother Cancer

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BackgroundMultiple synergistic combination approaches with cancer drugs are developed to overcome primary resistance to immunotherapy; however, the mechanistic rationale to combine chemoradiotherapy (CRT) with immune checkpoint inhibitors remains elusive.MethodsThis study described the immunological landscape of tumor microenvironment (TME) exposed to CRT. Tumor samples from patients with rectal cancer (n=43) treated with neoadjuvant CRT or radiotherapy were analyzed by nanostring and immunohistochemistry. Studies in mice were performed using three syngeneic tumors (TC1, CT26 and MC38). Tumor-bearing mice were treated either with platinum-based CRT, radiotherapy or chemotherapy. Anti-CTLA-4 and/or anti-Programmed Cell Death Receptor-1 (PD-1) therapy was used in combination with CRT. The therapy-exposed TME was screened by RNA sequencing and flow cytometry and tumor-infiltrating T lymphocyte functionality was evaluated by interferon (IFN)-γ ELIspot and intracellular cytokine staining.ResultsFront-to-front comparison analysis revealed the synergistic effect of CRT to establish a highly inflamed and Th1-polarized immune signature in the TME of patients and mice. In both settings, CRT-exposed TMEs were highly enriched in newly-infiltrated tumor-specific CD8+ T cells as well as tissue resident memory CD103+CD8+ T cells. In mice, CD8 T cells were involved in the antitumor response mediated by CRT and were primed by CRT-activated CD103+ dendritic cells. In the three tumor models, we showed that concurrent combination of CRT with a dual CTLA-4 and PD-1 blockade was required to achieve an optimal antitumor effect and to establish a broad and long-lasting protective antitumor T cell immunity.ConclusionsOur results highlight the ability of CRT to stimulate strong antitumor T-cell-mediated immunity and tissue resident memory T activation in TME, to foster immune checkpoint inhibitors action. These findings have implications in clinic for the design clinical trials combining chemoradiation with immunotherapy.

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Section: Patientsmentioning

confidence: 99%

Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

Joseph

Kirilovsky

Lecoester

et al. 2021

J Immunother Cancer

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“…PD-1 checkpoint blockade is a highly effective immune therapeutic that re-activates exhausted CD8 T cells during persistent infection (Barber et al, 2006;Hashimoto et al, 2018) and across a variety of cancers (Sharma et al, 2021;Wei et al, 2017). Despite their nonexhausted state, TFH cells (Ansel et al, 1999;Fazilleau et al, 2009;Vinuesa et al, 2005) and their follicular regulatory counterpart (TFR) (Gonzalez-Figueroa et al, 2021;Linterman et al, 2011;Wu et al, 2020) both express PD-1 with highest levels on GC localized subsets (Haynes et al, 2007;Shulman et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

Shuparski

et al. 2021

Preprint

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Adaptive B cell immunity to environmental antigens must be regulated by multiple CD4 T cell dependent tolerance mechanisms. Using integrated single cell strategies, we demonstrate that acute PD-1 blockade induces extensive and selective local anti-inflammatory IgG1 plasma cell (PC) differentiation. Expansion of pre-existing IgG1 germinal center (GC) B cell and enhanced GC programming without memory B cell involvement reveals an isotype-specific GC checkpoint that blocks steady-state IgG1 antibody maturation. While there was no adjuvant impact on immunization, acute PD-1 checkpoint blockade exaggerates anti-commensal IgG1 antibody production, alters microbiome composition and exerts its action in a CD4 T cell dependent manner. These findings reveal a PD-1 controlled adaptive B cell tolerance checkpoint that selectively constrains maturation of pre-existing anti-inflammatory antibodies to prevent over-reaction to steady-state foreign antigens.

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“…The last several years have also seen the rapid availability of immunotherapy drugs that increase overall survival in patients with a variety of cancers, including genitourinary malignancies (7). Immunotherapy utilizes the patient's immune system to induce tumor cell killing and can be either active or passive in nature.…”

Section: Introductionmentioning

confidence: 99%

Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies

Ukleja

Kusaka²,

Miyamoto³

2021

Front. Oncol.

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Immunotherapy drugs have recently been approved by the Food and Drug Administration for the treatment of several genitourinary malignancies, including bladder cancer, renal cancer, and prostate cancer. Preclinical data and early clinical trial results suggest that immune checkpoint inhibitors can act synergistically with radiation therapy to enhance tumor cell killing at local irradiated sites and in some cases at distant sites through an abscopal effect. Because radiation therapy is commonly used in the treatment of genitourinary malignancies, there is great interest in testing the combination of immunotherapy with radiation therapy in these cancers to further improve treatment efficacy. In this review, we discuss the current evidence and biological rationale for combining immunotherapy with radiation therapy, as well as emerging data from ongoing and planned clinical trials testing the efficacy and tolerability of this combination in the treatment of genitourinary malignancies. We also outline outstanding questions regarding sequencing, dose fractionation, and biomarkers that remain to be addressed for the optimal delivery of this promising treatment approach.

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The Next Decade of Immune Checkpoint Therapy

Cited by 386 publications

References 224 publications

Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

Chemoradiation triggers antitumor Th1 and tissue resident memory-polarized immune responses to improve immune checkpoint inhibitors therapy

PD-1 checkpoint blockade disrupts CD4 T cell regulated adaptive B cell tolerance to foreign antigens

Immunotherapy Combined With Radiation Therapy for Genitourinary Malignancies

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