Combination of Immune Checkpoint Therapy with Cellular Immunotherapy

Immune checkpoint blockade (ICB) therapy can elicit durable clinical responses by reactivating an exhausted immune response. However, single ICB therapy is limitedly effective due to the lack of a tumor-reactive immune infiltrate. Chimeric antigen receptor T (CAR-T) cell therapy can effectively remedy this lack by providing the necessary tumor-targeting immune infiltrate and a highly specific antitumor immune response. The efficacy of CAR-T cell therapy can be amplified by adding ICB agents, which can counteract the immune inhibitory environment undermining optimal CAR T cell efficacy.

Importance of Combination Therapy

Adoptive cell therapy, especially CAR-T cell therapy and monoclonal antibody (mAb)-based ICB therapy, have proven to be effective in various malignancies by harnessing the power of the immune system to recognize and eliminate cancer cells. However, when used as monotherapies, these therapies only have less marked therapeutic effects. Accumulating evidence has demonstrated that tumors may evade immune surveillance by stimulating immune checkpoint inhibitory receptors on T cells, including CTLA-4 and PD-1. This stimulation induced the immunosuppressive microenvironment that limits the efficacy of CAR-T cell therapy. Therefore, using antibodies that block these inhibitory immune checkpoints is a promising approach to increase the beneficial effect of CAR-T treatment in solid tumors.

Rejuvenate of CAR T cell Exhaustion with Checkpoint Inhibitors

To overcome immune suppression in the tumor microenvironment, checkpoint inhibitors are used to rejuvenate exhausted CAR T cells. Scientists have revealed that up-regulation of specific checkpoint ligands such as PD-L1 will induce premature CAR T cell exhaustion. Inversely, PD-1 and/or PD-L1 antagonistic antibodies intercepting PD-1 checkpoint can rescue CAR T cells from exhaustion and improve their cytolytic activity in melanoma.

Fig.1 Mechanisms of the rescue of CAR T cell exhaustion with checkpoint blockade. (Grosser, 2019)

Cases of Combination Therapy

Combination therapy strategies based on CAR‑T cell therapies and ICB have been widely studied in preclinical studies or clinical trials and have yielded encouraging results. CAR-T cell therapy and immune checkpoint blockade are highly synergistic, leading to long-term survival without causing any signs of pathology in vivo.

Immune Checkpoint Drug Development Services

Immune checkpoint molecules have been recognized as promising anti-cancer targets, and their incorporation with CAR-T cell therapy has attracted considerable interest in biological and preclinical studies. As a leader in immune checkpoint research and product development, Creative Biolabs provides a comprehensive range of customized, high-quality services in immune checkpoint antibodies, proteins, peptides, assays, and small molecule drug development to support the pharmaceutical industry and related biomedical sciences research communities worldwide. Our expert team has years of experience and will work with you to ensure the developed products meet your requirements.

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Reference

1. Grosser, R.; et al. Combination immunotherapy with CAR T cells and checkpoint blockade for the treatment of solid tumors. Cancer Cell. 2019, 36(5): 471-482.

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