CA-170 – A Potent Small-Molecule PD-L1 Inhibitor or Not?

Musielak, Bogdan; Kocik, Justyna; Skalniak, Łukasz; Magiera‐Mularz, Katarzyna; Sala, Dominik; Czub, Miroslawa; Stec, Małgorzata; Siedlar, Maciej; Holak, Tad A.; Plewka, Jacek

doi:10.3390/molecules24152804

Cited by 112 publications

(89 citation statements)

References 43 publications

(52 reference statements)

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“…One of the first agents to move into the clinic is a small molecule, CA‐170, developed by Aurigene and licensed by Curis. CA‐170 is an oral PD‐L1, PD‐L2 and VISTA checkpoint antagonist that has been shown to interfere with the suppression of T cell activation and cytokine production by VISTA . Clinical development (NCT02812875) of CA‐170 is ongoing with evaluation of potentially pharmacologically active doses in VISTA‐expressing tumors.…”

Section: Vista Targeting Agents Under Developmentmentioning

confidence: 99%

VISTA: Coming of age as a multi-lineage immune checkpoint

ElTanbouly

Schaafsma

Noelle

et al. 2020

Clinical and Experimental Immunology

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The immune response is governed by a highly complex set of interactions among cells and mediators. T cells may be rendered dysfunctional by the presence of high levels of antigen in the absence of co-stimulation while myeloid cells may be programmed towards an immunosuppressive state that promotes cancer growth and metastasis while deterring tumor immunity. In addition, inhibitory programs driven by immune checkpoint regulators dampen anti-tumor immunity. The ideal cancer immunotherapy treatment will improve both cross-priming in the tumor microenvironment and relieve suppression by the inhibitory checkpoints. Recently, blockade of programmed cell death 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) has elicited impressive results, but not in all patients, so additional targets are under investigation. V-set immunoglobulin domain suppressor of T cell activation (VISTA) is a novel immunoregulatory receptor that is broadly expressed on cells of the myeloid and lymphoid lineages, and is frequently implicated as a poor prognostic indicator in multiple cancers. Importantly, antibody targeting of VISTA uniquely engages both innate and adaptive immunity. This, combined with the expression of VISTA and its non-redundant activities compared to other immune checkpoint regulators, qualifies VISTA to be a promising target for improving cancer immunotherapy.

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Section: Vista Targeting Agents Under Developmentmentioning

confidence: 99%

VISTA: Coming of age as a multi-lineage immune checkpoint

ElTanbouly

Schaafsma

Noelle

et al. 2020

Clinical and Experimental Immunology

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“…Its blockage reduces adaptive Tregs, impairs their suppressive function and potentiates both tumour-specific T cells activation and APCs inflammatory response. 26 The molecular bases of such effects are not fully understood, 36 even if evidence supports both T-cell extrinsic and intrinsic role of VISTA, and putative ligands have recently been discovered. 6 7 37 The development of VISTA inhibitors, notably CA-170 that is the first small molecule targeting PD-1/PD-L1 axis entering the clinical research, retains some interesting aspects: the possibility of simultaneous multimolecules blockage, working at multiple levels on immune-surveillance mechanisms; the oral route of administration, which simplify patient's management and reduces risks related to infusion; the potential good activity in tumours with high VISTA expression, but low PD-L1 expression (eg, MPM).…”

Section: Discussionmentioning

confidence: 99%

New emerging targets in cancer immunotherapy: the role of VISTA

2019

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The immune surveillance system is complex and regulated by different actors. Programmed death protein-ligand 1 (PD-L1), the only approved biomarker in clinical practice, has proven to be imperfect in selecting patients to immune checkpoint inhibitors treatment. Therefore, new biomarkers, and new therapeutic targets, are needed to maximise the efficacy of immunotherapy. V-domain Ig Suppressor of T-cell Activation (VISTA) is a programmed death protein-1 (PD-1) homolog expressed on T cells and on antigen-presenting cells, which regulates processes of activation and repression of the immune system with not yet completely clarified mechanisms. Its blockage has demonstrated in vitro and in vivo antitumour activity. The clinical research of VISTA antagonists is ongoing. Particularly, CA-170, an orally delivered dual inhibitor of VISTA and PD-L1, has shown to have clinical efficacy in phase I and II clinical trials in different advanced solid tumour types. Further data are needed to define whether this drug class can become a new therapeutic option for patients with VISTA expressing cancers.

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“…The blockage of VISTA and PD-1 through the use of a small molecule, called CA-170, increases T-cell activation and IFN-γ production by T cells [95]. Still, in Krakow, Musielak et al [96] have shown that CA-170 has no interaction with PD-1/PD-L1 and state that this previously potential clinical application must be further investigated [96].…”

Section: Therapeutic Targets For T or B Cell Subpopulations In Lymphomamentioning

confidence: 99%

“…More details on the role of the abovementioned biomarkers, viewed as therapeutic targets, as well as the currently available immune checkpoint inhibitors, and development and testing stages are presented in Table 2 [96][97][98][99][100][101][102][103][104].…”

Section: Therapeutic Targets For T or B Cell Subpopulations In Lymphomamentioning

confidence: 99%

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

Desmirean

Rauch

Jurj

et al. 2020

JCM

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Malignant lymphomas are a heterogeneous group of malignancies that develop both in nodal and extranodal sites. The different tissues involved and the highly variable clinicopathological characteristics are linked to the association between the lymphoid neoplastic cells and the tissues they infiltrate. The immune system has developed mechanisms to protect the normal tissue from malignant growth. In this review, we aim to explain how T lymphocyte-driven control is linked to tumor development and describe the tumor-suppressive components of the resistant framework. This manuscript brings forward a new insight with regard to intercellular and intracellular signaling, the immune microenvironment, the impact of therapy, and its predictive implications. A better understanding of the key components of the lymphoma environment is important to properly assess the role of both B and T lymphocytes, as well as their interplay, just as two legendary boxers face each other in a heavyweight title final, as was the case of Ali versus Foreman.

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CA-170 – A Potent Small-Molecule PD-L1 Inhibitor or Not?

Cited by 112 publications

References 43 publications

VISTA: Coming of age as a multi-lineage immune checkpoint

VISTA: Coming of age as a multi-lineage immune checkpoint

New emerging targets in cancer immunotherapy: the role of VISTA

B Cells versus T Cells in the Tumor Microenvironment of Malignant Lymphomas. Are the Lymphocytes Playing the Roles of Muhammad Ali versus George Foreman in Zaire 1974?

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