Immune checkpoint blockade is able to induce durable responses across multiple types of cancer, which has enabled the oncology community to begin to envision potentially curative therapeutic approaches. However, the remarkable responses to immunotherapies are currently limited to a minority of patients and indications, highlighting the need for more effective and novel approaches. Indeed, an extraordinary amount of preclinical and clinical investigation is exploring the therapeutic potential of negative and positive costimulatory molecules. Insights into the underlying biological mechanisms and functions of these molecules have, however, lagged significantly behind. Such understanding will be essential for the rational design of next-generation immunotherapies. Here, we review the current state of our understanding of T-cell costimulatory mechanisms and checkpoint blockade, primarily of CTLA4 and PD-1, and highlight conceptual gaps in knowledge. Significance: This review provides an overview of immune checkpoint blockade therapy from a basic biology and immunologic perspective for the cancer research community. Cancer Discov; 8(9); 1069–86. ©2018 AACR.

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Fundamental Mechanisms of Immune Checkpoint Blockade Therapy

The T lymphocyte, especially its capacity for antigen-directed cytotoxicity, has become a central focus for engaging the immune system in the fight against cancer. Basic science discoveries elucidating the molecular and cellular biology of the T cell have led to new strategies in this fight, including checkpoint blockade, adoptive cellular therapy and cancer vaccinology. This area of immunological research has been highly active for the past 50 years and is now enjoying unprecedented bench-to-bedside clinical success. Here, we provide a comprehensive historical and biological perspective regarding the advent and clinical implementation of cancer immunotherapeutics, with an emphasis on the fundamental importance of T lymphocyte regulation. We highlight clinical trials that demonstrate therapeutic efficacy and toxicities associated with each class of drug. Finally, we summarize emerging therapies and emphasize the yet to be elucidated questions and future promise within the field of cancer immunotherapy.

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A guide to cancer immunotherapy: from T cell basic science to clinical practice.

Immunotherapies are the most rapidly growing drug class and have a major impact in oncology and on human health. It is increasingly clear that the effectiveness of immunomodulatory strategies depends on the presence of a baseline immune response and on unleashing of pre-existing immunity. Therefore, a general consensus emerged on the central part played by effector T cells in the antitumour responses. Recent technological, analytical and mechanistic advances in immunology have enabled the identification of patients who are more likely to respond to immunotherapy. In this Review, we focus on defining hot, altered and cold tumours, the complexity of the tumour microenvironment, the Immunoscore and immune contexture of tumours, and we describe approaches to treat such tumours with combination immunotherapies, including checkpoint inhibitors. In the upcoming era of combination immunotherapy, it is becoming critical to understand the mechanisms responsible for hot, altered or cold immune tumours in order to boost a weak antitumour immunity. The impact of combination therapy on the immune response to convert an immune cold into a hot tumour will be discussed.

Approaches to treat immune hot, altered and cold tumours with combination immunotherapies

Tumour cells evade immune surveillance by upregulating the surface expression of programmed death-ligand 1 (PD-L1), which interacts with programmed death-1 (PD-1) receptor on T cells to elicit the immune checkpoint response1,2. Anti-PD-1 antibodies have shown remarkable promise in treating tumours, including metastatic melanoma2–4. However, the patient response rate is low4,5. A better understanding of PD-L1-mediated immune evasion is needed to predict patient response and improve treatment efficacy. Here we report that metastatic melanomas release extracellular vesicles, mostly in the form of exosomes, that carry PD-L1 on their surface. Stimulation with interferon-γ (IFN-γ) increases the amount of PD-L1 on these vesicles, which suppresses the function of CD8 T cells and facilitates tumour growth. In patients with metastatic melanoma, the level of circulating exosomal PD-L1 positively correlates with that of IFN-γ, and varies during the course of anti-PD-1 therapy. The magnitudes of the increase in circulating exosomal PD-L1 during early stages of treatment, as an indicator of the adaptive response of the tumour cells to T cell reinvigoration, stratifies clinical responders from non-responders. Our study unveils a mechanism by which tumour cells systemically suppress the immune system, and provides a rationale for the application of exosomal PD-L1 as a predictor for anti-PD-1 therapy. Melanoma cells release programmed death-ligand 1 (PD-L1) on the surface of circulating exosomes, suggesting a mechanism by which tumours could evade the immunesystem, and the potential application of exosomal PD-L1 to monitor patient responses to checkpoint therapies.

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Exosomal PD-L1 Contributes to Immunosuppression and is Associated with anti-PD-1 Response

Regulation and Function of the PD-L1 Checkpoint

Programmed cell death–1 (PD-1) is a coinhibitory receptor that suppresses T cell activation and is an important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to suppress signaling through the T cell receptor (TCR). By titrating PD-1 signaling in a biochemical reconstitution system, we demonstrate that the co-receptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1–recruited Shp2 phosphatase. We also show that CD28, but not the TCR, is preferentially dephosphorylated in response to PD-1 activation by PD-L1 in an intact cell system. These results reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting that costimulatory pathways play key roles in regulating effector T cell function and responses to anti–PD-L1/PD-1 therapy.

/pdf/t-cell-costimulatory-receptor-cd28-is-a-primary-target-for-2p9of7q5bp.pdf

T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.

Programmed death-1 (PD-1) is a co-inhibitory receptor that suppresses T cell activation and is an
important cancer immunotherapy target. Upon activation by its ligand PD-L1, PD-1 is thought to
suppress signaling through the T cell receptor (TCR). Here, by titrating the strength of PD-1
signaling in both biochemical reconstitution systems and in T cells, we demonstrate that the
coreceptor CD28 is strongly preferred over the TCR as a target for dephosphorylation by PD-1-
recruited Shp2 phosphatase. We also show that PD-1 colocalizes with the costimulatory receptor
CD28 in plasma membrane microclusters but partially segregates from the TCR. These results
reveal that PD-1 suppresses T cell function primarily by inactivating CD28 signaling, suggesting
that costimulatory pathways may play unexpected roles in regulating effector T cell function and
therapeutic responses to anti-PD-L1/PD-1.

/pdf/t-cell-co-stimulatory-receptor-cd28-is-a-primary-target-for-2klyue3e0v.pdf

T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition


 Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to gauge safety and identify early efficacy signals in treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti-PD-L1) was evaluated with ipat, an oral AKT inhibitor, with (M-HR+ BC) and without (M-TNBC) fulv. Methods: In 2 separate randomized trials, eligible immune checkpoint inhibitor naive pts with either 2L/3L HR+ chemotherapy-naive BC who had prior CDK4/6 inhibitor treatment or 2L TNBC, received atezo (840 mg D1, 15) with ipat (400 mg D1-21); pts with HR+ BC also received fulv monthly. Control tx for M-HR+ BC (NCT03280563) was fulv and for M-TNBC (NCT03424005) was capecitabine; given the adaptive nature of the MORPHEUS platform only some of the control arm pts were enrolled concurrently with pts in the ipat arms for M-HR+ BC. Primary endpoints were ORR (overall response rate; investigator-assessed RECIST 1.1) and safety. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results: Median duration of survival follow-up was 7.6 months for M-HR+ BC (data cutoff: Aug 2020) and 10.8 for M-TNBC (data cutoff: Mar 2021). In M-HR+ BC, none of whom received prior fulvestrant, 26 pts received atezo + ipat + fulv and 15 received fulv. Confirmed ORRs were 23.1% (95% CI: 9.0, 43.7) and 0% (95% CI: 0, 21.8), respectively. Median PFS was 4.4 mo (95% CI: 1.6, not evaluable) and 1.9 mo (95% CI: 1.6, 3.9), respectively. Updated survival data will be presented. Respectively, 61.5% and 20.0% of pts had Gr 3-4 AEs; no G5 AEs were observed; serious AEs (SAEs) occurred in 38.5% and 13.3% of pts; 7.7% and 0% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (73.0%), diarrhea (53.8%), nausea (42.3%), fatigue (26.9%), vomiting (23.1%), decreased appetite (19.2%), headache (15.4%), pyrexia (11.5%), hyperglycemia (11.5%), and aspartate aminotransferase (AST) increase (11.5%), in the combination arm; of these, rash (38.4%), diarrhea (7.7%), and AST increase (7.7%) included Grade 3-4 tx-related AEs. In M-TNBC, 29 pts received atezo + ipat and 24 received capecitabine. Confirmed ORRs were 3.4% (95% CI: 0.1, 17.8) and 20.8% (95% CI: 7.1, 42.2), respectively. Median PFS was 1.7 mo (95% CI: 1.5, 2.8) and 4.1 mo (95% CI: 2.3, 5.7), respectively. Median OS was 10.8 mo (95% CI: 7.0, 18.1) and 15.2 mo (95% CI: 14.4, 20.8). Gr 3-4 AEs were seen in 51.7% and 37.5% of pts, respectively; Gr 5 AEs were seen in 1 pt in the combination arm (encephalitis due to atezo). SAEs occurred in 51.7% and 16.7% of pts, respectively; 6.9% and 4.2% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (55.2%), diarrhea (48.3%), nausea (37.9%), pyrexia (31.0%), and fatigue (24.1%) in the combination arm; of these, rash (24.1%), fatigue (3.4%), and pyrexia (3.4%) included Gr 3-4 tx-related AEs. Biomarker data, including PI3K pathway status, PD-L1 and CD8-panCK expression, will also be presented. Conclusion: Atezo + ipat + fulv was tolerable with a preliminary efficacy signal in HR+ BC. Atezo + ipat had limited efficacy in biomarker unselected TNBC.
 Citation Format: Sara A. Hurvitz, Valentina Boni, Elizabeth Comen, Seock-Ah Im, Kyung Hae Jung, Sung-Bae Kim, Keun Seok Lee, Sherene Loi, Hope S. Rugo, Amir Sonnenblick, Melinda L. Telli, Kelly DuPree, Marcella Fasso, Ya-Chen Lin, Mina Nikanjam, Frauke Schimmoller, Xiaosong Zhang, Jing Zhu, Peter Schmid. Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-04.

Abstract PD10-04: Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC)

Jing Zhu

Papers

T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition.

T cell co-stimulatory receptor CD28 is a primary target for PD-1-mediated inhibition

Abstract PD10-04: Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC)