CTLA-4 Blockade for Cancer Therapy
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) has demonstrated promise in a variety of malignancies. Creative Biolabs has extensive experience in the field of cancer vaccines and can provide CTLA-4 blockade development services for the treatment of cancer with durable responses and extended overall survival.
Biological Function of CTLA-4
CTLA-4 is the first clinically targeted immune checkpoint receptor. Typically, after T cell activation, CTLA-4 is upregulated on the plasma membrane where it functions to downregulate T cell function through a variety of mechanisms, including preventing costimulation by outcompeting CD28 for its ligand, B7, and also by inducing T-cell cycle arrest. CTLA-4 plays an important role in maintaining normal immune homeostasis because CTLA-4 deficient mice die from lethal lymphocyte proliferation. Recognizing the role of CTLA-4 as a negative regulator of immunity, studies have shown that antibody blockade of CTLA-4 can produce anti-tumor immunity in preclinical models.
Fig.1 The cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) immunologic checkpoint. (Postow MA. 2015)
CTLA-4 and Cancer
CTLA-4 plays an important role in restraining the adaptive immune response of T-cells towards a variety of antigens including tumor associated antigens (TAAs). The blockade of this immune checkpoint elicits an effective anti-cancer immune response in a series of preclinical models, suggesting that naturally occurring (or therapeutically induced) TAA specific lymphocytes need to be "unleashed" to properly fight against malignant cells. This therapeutic hypothesis has also been tested in humans. The favorable outcome of this strategy in patients with advanced cutaneous melanoma are revolutionizing the management of this highly aggressive disease and are fueling new enthusiasm for cancer immunotherapy.
Development of CTLA-4 inhibitors as a form of cancer immunotherapy
Shortly after the discovery of the inhibitory function of CTLA-4, antibody-mediated blockade of CTLA-4 function was found to enhance the rejection of transplanted mouse colon carcinoma and fibrosarcoma tumors and additionally, delay growth of established tumors. In addition, anti-CTLA-4 treatment resulted in immune memory, allowing previously challenged mice to reject subsequently implanted tumors without additional CTLA-4 blockade. The anti-tumor effects of CTLA-4 blockade have been extended to many other mouse tumor models, including renal cell cancer, prostate cancer, and lymphoma.
Combination Approaches
To improve on the number of patients who benefit from immune checkpoint blockade, CTLA-4 and PD-1/PD-L1 antibodies are combined together and with other anticancer agents (e.g., targeted therapy, chemotherapy, radiation therapy, and other immunotherapies). Many of these combination approaches are based on a strong scientific background, but data from randomized studies are not yet available to show that any specific combination approach is more efficacious than single-agent CTLA-4 or PD-1/PD-L1 blockade.
Fig.2 Unique spatiotemporal regulation of CTLA-4 and PD-1. (Intlekofer AM. 2013)
Creative Biolabs is a leader in the field of vaccine development and has focused on the cancer vaccines for years. We have experienced experts and advanced platforms that are able to provide excellent services. If you are interested in our services, please contact us for more details.
References
- Postow MA. (2015). “Immune Checkpoint Blockade in Cancer Therapy.” J Clin Oncol. 33(17): 1974-82.
- Intlekofer AM. (2013). “At the bench: preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy.” J Leukoc Biol. 94(1): 25-39.
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