Beyond CTLA-4 and PD-1 Inhibition: Novel Immune Checkpoint Molecules for Melanoma Treatment

Abstract

More than ten years after the approval of ipilimumab, immune checkpoint inhibitors (ICIs) against PD-1 and CTLA-4 have been established as the most effective treatment for locally advanced or metastatic melanoma, achieving durable responses either as monotherapies or in combinatorial regimens. However, a considerable proportion of patients do not respond or experience early relapse, due to multiple parameters that contribute to melanoma resistance. The expression of other immune checkpoints beyond the PD-1 and CTLA-4 molecules remains a major mechanism of immune evasion. The recent approval of anti-LAG-3 ICI, relatlimab, in combination with nivolumab for metastatic disease, has capitalized on the extensive research in the field and has highlighted the potential for further improvement of melanoma prognosis by synergistically blocking additional immune targets with new ICI-doublets, antibody–drug conjugates, or other novel modalities. Herein, we provide a comprehensive overview of presently published immune checkpoint molecules, including LAG-3, TIGIT, TIM-3, VISTA, IDO1/IDO2/TDO, CD27/CD70, CD39/73, HVEM/BTLA/CD160 and B7-H3. Beginning from their immunomodulatory properties as co-inhibitory or co-stimulatory receptors, we present all therapeutic modalities targeting these molecules that have been tested in melanoma treatment either in preclinical or clinical settings. Better understanding of the checkpoint-mediated crosstalk between melanoma and immune effector cells is essential for generating more effective strategies with augmented immune response.

T cell-mediated tumor killing sensitivity gene signature-based prognostic score for acute myeloid leukemia

“…The low TTKPI group showed higher levels of CD160, CD200, CD47, CD96, TMIGD2, and lower levels of C10orf54, CD276, CD86, KIR3DL1, LAG3, LGALS9, PDCD1, SELPLG, SIGLEC7, TNFRSF8. Classical immune checkpoint inhibitor drugs targeting PD-1, PD-L1 and CTLA4 show variable efficacy and additional checkpoint inhibitor drugs such as drugs targeting LAG3 are under current focus [ 67 , 68 ]. Our data suggest that the TTKPI score pattern could potentially direct the selection of optimal checkpoint inhibitor drugs and combination.…”

“…TTKPI negatively correlated with CD4 naïve and follicular helper T cell immune infiltration scores while M2 macrophages, monocytes were positively correlated, implying a T cell exhausted, comparatively pro-inflammatory, innate immune dominated milieu in high TTKPI states, which corresponded to low survival. T cell exhaustion and concurrent PD-1 resistance is a characteristic of severe AML [ 67 , 68 ]. An AML tumor immune landscape marked by high M2 macrophage and monocyte infiltration corresponds to high inflammatory response and predicts poor survival [ 69 ], in alignment with our results.…”

New Emerging Targets in Cancer Immunotherapy: The Role of B7-H3

“…Following the high efficacy of first-generation CPIs, the expression of further checkpoint molecules beyond PD-1 and CTLA-4 and their involvement in the immune manipulation has become the focus of extensive preclinical and clinical research [ 5 ]. Although the marked immunogenicity of melanoma initially stimulates an effective antitumor immune response, the expression of IC molecules is a well-documented phenomenon that leads to T-cell exhaustion and allows for immunosurveillance evasion and immunotherapy resistance [ 4 ].…”

“…However, a considerable percentage of subjects experience minimal benefit or present with early relapse owing to numerous events that curtail CPI-enhanced immunosurveillance. Upregulation of additional IC molecules beyond PD-1/PD-L1 and CTLA-4 was a well-described mechanism of resistance that has fueled the research interest on identifying novel ICs that could improve treatment outcomes and render immunotherapy beneficial for a larger set of cancer patients [ 3 , 4 , 5 ]. In the present review, we focus on the role of B7-H3 in different solid malignancies.…”

Design, Synthesis, and Antitumor Activity Evaluation of Novel VISTA Small Molecule Inhibitors

“…While antibody-based inhibitors targeting VISTA have advanced to clinical trials, the development of small molecule inhibitors remains limited, and there is an urgent need to discover potent candidates with well-defined structure–activity relationship. Compound 1 ( CA-170 ) is reported as a dual-targeting small molecule inhibitor of PD-L1 and VISTA by Aurigene company and currently in phase II clinical trial .…”