PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy

Sasikumar, Pottayil G.; Sudarshan, Naremaddepalli S.; Adurthi, Srinivas; Ramachandra, Raghuveer K.; Samiulla, Dodderi S.; Lakshminarasimhan, Anirudha; Ramanathan, Anuradha; Chandrasekhar, T.; Dhudashiya, Amit A.; Talapati, Sumalatha Rani; Gowda, Nagesh; Palakolanu, Sreenivasulareddy; Mani, Jiju; Srinivasrao, Bandi; Joseph, David; Kumar, Nigam; Nair, Rashmi; Atreya, Hanudatta S.; Gowda, Nagaraj; Ramachandra, Murali

doi:10.1038/s42003-021-02191-1

Cited by 98 publications

(79 citation statements)

References 50 publications

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“…VISTA (V-domain immunoglobulin suppressor of T –cell activation) is a type I transmembrane protein able to suppress T-cell activation, with sequence homology with PD-1 and PD-L1 ( 58 ). This has permitted the development of an oral dual inhibitor (PD-L1 and VISTA) CA-170, which showed an interesting activity and safety profile in pretreated but ICI naive NSCLC, with a dosage of 400 mg daily ( 59 , 60 ).…”

Section: Overcoming Immunotherapy Resistancementioning

confidence: 99%

The Landscape of Immunotherapy Resistance in NSCLC

et al. 2022

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Lung cancer is the leading cause of cancer mortality worldwide. Immunotherapy has demonstrated clinically significant benefit for non-small-cell lung cancer, but innate (primary) or acquired resistance remains a challenge. Criteria for a uniform clinical definition of acquired resistance have been recently proposed in order to harmonize the design of future clinical trials. Several mechanisms of resistance are now well-described, including the lack of tumor antigens, defective antigen presentation, modulation of critical cellular pathways, epigenetic changes, and changes in the tumor microenvironment. Host-related factors, such as the microbiome and the state of immunity, have also been examined. New compounds and treatment strategies are being developed to target these mechanisms with the goal of maximizing the benefit derived from immunotherapy. Here we review the definitions of resistance to immunotherapy, examine its underlying mechanisms and potential corresponding treatment strategies. We focus on recently published clinical trials and trials that are expected to deliver results soon. Finally, we gather insights from recent preclinical discoveries that may translate to clinical application in the future.

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Section: Overcoming Immunotherapy Resistancementioning

confidence: 99%

The Landscape of Immunotherapy Resistance in NSCLC

et al. 2022

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“…In addition, studies have found that patients who show resistance to PD-1/CTLA-4-targeting therapies may benefit from VSIR blockade ( Kong et al, 2021 ). Moreover, CA-170, an orally administered dual inhibitor of VISTA and PD-L1, has shown clinical efficacy in phase I and II clinical trials in several advanced solid tumor types ( Sasikumar et al, 2021 ). This paper comprehensively explored the relationship between VSIR and other immune checkpoints.…”

Section: Discussionmentioning

confidence: 99%

Identify the Prognostic and Immune Profile of VSIR in the Tumor Microenvironment: A Pan-Cancer Analysis

Liu

Zhang

Wang

et al. 2022

Front. Cell Dev. Biol.

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VSIR is a critical immunomodulatory receptor that inhibits T cell effector function and maintains peripheral tolerance. However, the mechanism by which VSIR participates in tumor immunity in the pan-cancer tumor microenvironment remains unclear. This study systematically explored the prognostic and immune profile of VSIR in the tumor microenvironment of 33 cancers. We compared the expression patterns and molecular features of VSIR in the normal and cancer samples both from the public databases and tumor chips. VSIR level was significantly related to patients’ prognosis and could be a promising predictor in many tumor types, such as GBM, KIRC, SKCM, READ, and PRAD. Elevated VSIR was closely correlated with infiltrated inflammatory cells, neoantigens expression, MSI, TMB, and classical immune checkpoints in the tumor microenvironment. Enrichment signaling pathways analysis indicated VSIR was involved in several immune-related pathways such as activation, proliferation, and migration of fibroblast, T cell, mast cell, macrophages, and foam cell. In addition, VSIR was found to widely express on cancer cells, fibroblasts, macrophages, and T cells in many tumor types based on the single-cell sequencing analysis and co-express with M2 macrophage markers CD68, CD163 based on the immunofluorescence staining. Finally, we predicted the sensitive drugs targeting VSIR and the immunotherapeutic value of VSIR. In sum, VSIR levels strongly correlated with the clinical outcome and tumor immunity in multiple cancer types. Therefore, therapeutic strategies targeting VSIR in the tumor microenvironment may be valuable tools for cancer immunotherapy.

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“…Simultaneous targeting of more than one immune checkpoint proteins with the same agent because of the significant structural homology to drive greater response possible ( 19 , 20 )…”

Section: Opportunities For Small Molecule Agents To Address the Limit...mentioning

confidence: 99%

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

Sasikumar

Ramachandra

2022

Front. Immunol.

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Pioneering success of antibodies targeting immune checkpoints such as programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) has changed the outlook of cancer therapy. Although these antibodies show impressive durable clinical activity, low response rates and immune-related adverse events are becoming increasingly evident in antibody-based approaches. For further strides in cancer immunotherapy, novel treatment strategies including combination therapies and alternate therapeutic modalities are highly warranted. Towards this discovery and development of small molecule, checkpoint inhibitors are actively being pursued, and the efforts have culminated in the ongoing clinical testing of orally bioavailable checkpoint inhibitors. This review focuses on the small molecule agents targeting PD-1 checkpoint pathway for cancer immunotherapy and highlights various chemotypes/scaffolds and their characterization including binding and functionality along with reported mechanism of action. The learnings from the ongoing small molecule clinical trials and crucial points to be considered for their clinical development are also discussed.

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PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy

Cited by 98 publications

References 50 publications

The Landscape of Immunotherapy Resistance in NSCLC

The Landscape of Immunotherapy Resistance in NSCLC

Identify the Prognostic and Immune Profile of VSIR in the Tumor Microenvironment: A Pan-Cancer Analysis

Small Molecule Agents Targeting PD-1 Checkpoint Pathway for Cancer Immunotherapy: Mechanisms of Action and Other Considerations for Their Advanced Development

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