1. Kumar Das, Dibash PhD

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The paramount achievement in oncology in the last decade has certainly been the utilization of immune checkpoint inhibitors (ICIs) in becoming a powerful clinical strategy with a more holistic view of the patient.

Checkpoint Inhibitor... - Click to enlarge in new windowCheckpoint Inhibitors. Checkpoint Inhibitors

Cancers arise from malignantly transformed normal cells and progressively break the balance between the transformed cells and immunity via shaping the tumor immune microenvironment. The immune system is the core defense against cancer development and the goal of cancer immunotherapy is to manipulate the immune system to alter the balance between malignant cells and immunity. Consequently, to overcome these immunosuppressive conditions, ICI therapies have been developed to target the adaptive immune system, generating a T-cell anti-tumor response.


The most well-described checkpoints include the cytotoxic T lymphocyte-associated molecule-4 (CTLA- 4), programmed cell death receptor-1 (PD-1), and programmed cell death ligand-1 (PD-L1). ICIs targeting CTLA-4 and PD-1/PD-L1 have become a foundation in the management of cancer immunotherapy. Many ICIs targeting CTLA-4, PD-1, and its ligand PD-L1 have been developed and applied to clinical practice, such as ipilimumab, nivolumab, pembrolizumab, and atezolizumab. These ICIs are now used as single agents or in combination with chemotherapies for about 50 cancer types.


While immunotherapy has revolutionized the treatment of many types of advanced cancer, their overall clinical application status remains unsatisfactory and only a small percentage of patients have meaningful responses to these treatments. The challenges in improving the efficacy of ICIs include low response rate, primary or acquired resistance, and immune-related adverse events.


Insights on how to increase the response rates and overcome the resistance to the different classes of ICIs is the key to improving clinical efficacy. However, they continue to be an important treatment option in cancer care.


Finding New Leads

As part of a larger strategy to improve responses to immunotherapy and extend the application of ICI therapy to more types of cancers and patients, additional agents and inhibitory pathways are being explored.


Recently, a comprehensive review published in the Journal of Hematology & Oncology focused on Phase I and Phase II clinical trials using novel investigational molecules and ICI pathways that have emerged within the last 3 years (2021;


In the review, Marin-Acevedo and colleagues included information from 2018 to 2020 and reviewed both preliminary results of continuing trials, along with completed clinical trials. The group excluded Phase III or later stage clinical trials, immune stimulatory agents, immune cellular therapy, vaccines, viruses, studies involving the pediatric population, and trials that investigated well-known targets such as CTLA-4, PD-1, and/or PD-L1. Overall, they summarized 36 Phase I, nine Phase I/II, and seven Phase II clinical trials. The investigational molecules from the trials were categorized as inhibitory immune checkpoints or inhibitory targets beyond immune checkpoints based on whether the manipulation of the pathway has direct or indirect consequences on T-cell effects.


In brief, the inhibitory immune checkpoint targets reviewed include, but are not limited to the following:


* Lymphocyte activation gene-3 (LAG-3, CD223): A molecule that interacts with major histocompatibility complex (MHC) class II and is expressed by activated T cells, B cells, natural killers (NK) cells, and dendritic cells (DCs).


* T-cell immunoglobulin-3 (TIM-3): An immune checkpoint that stimulates immune tolerance and is expressed by numerous cells including effector T cells, Tregs, B cells, NK cells, DCs, macrophages, as well as tumor cells.


* B7-H3 and B7-H4: Members of the B7 superfamily of ligands interact with the CD28-receptor family to either modulate stimulatory or inhibitory immune signals.


* PVRIG/PVRL2: Poliovirus receptor-related immunoglobulin domain containing (PVRIG) is a novel protein and member of the immunoglobulin superfamily receptors.



Inhibitory targets beyond immune checkpoints reviewed include, but are not limited to the following:


* CEACAM1, CEACAM5, CEACAM6: Carcinoembryonic antigen-related cell adhesion molecules (CEACAMs) is a family of proteins that facilitate different physiological effects varying from immune modulation to tissue organization and angiogenesis.


* CCL2/CCR2: Chemokine CCL2 and its main receptor CCR2 have roles in cancer pathogenesis which include recruiting immunosuppressive cells that promote angiogenesis, and facilitating tumor growth, proliferation, and metastasis.


* Leukemia inhibitory factor (LIF): A vital peptide in embryogenesis which promotes an immunosuppressive microenvironment that safeguards the embryo from the mother's immune system.


* CD47/SIRP[alpha]: CD47 is expressed by virtually all normal tissue and works as a marker of self-recognition. Once bound to the transmembrane protein "signal regulatory protein alpha" (SIRP[alpha]) situated on the surface of macrophages, CD47 triggers an anti-phagocytic signal.


* IL-8 (CXCL8): An inflammatory chemokine that functions in the regulation of angiogenesis, tumor cell motion, leukocyte infiltration, cancer cell growth and survival, and modification of immune responses.


* Semaphorins/SEMA4D: Semaphorins are a family of transmembrane proteins that support with axonal repair after neuronal injury, cytoskeletal changes, and migration of endothelial and immune cells.


* Ang-1 and 2: Angiopoietins are growth factors with roles in the maintenance of vascular integrity, vascular homeostasis, and growth. While both molecules act on the same receptor, Tie2, they have reverse effects.



With numerous treatment options in clinical and preclinical development, the hopes are promising that ICI regimens and new combinations will be identified and optimized to revolutionize immune-based cancer therapies once again.


Dibash Kumar Das is a contributing writer.