In the pursuit of disrupting tumor growth, a groundbreaking approach emerges through dendritic cell (DC) vaccines that target tumor-derived blood vessels, unleashing potent immune responses to combat cancer. While early vaccine generations showed hope in pre-clinical models, clinical outcomes have been disappointing. However, the success of Sipuleucel-T has revitalized interest in DC vaccines, and this review delves into their potential.
Tumor-derived blood vessels, sustained by VEGF, can hamper DC function. This includes hindering mature DC mobility, reducing MHC class II expression, and inducing PD-L1 on myeloid DCs, suppressing immune response. Although VEGF-specific antibodies and small molecule drugs have been approved, monotherapies often face resistance due to tumor blood vessels adapting to other growth factors. Combining VEGF blockade with chemotherapy, ICIs, or mTOR inhibitors shows improved anti-tumor effects.
While DC vaccines alone may have limitations, innovative strategies like vascular normalization can enhance their potential. By restoring blood flow dynamics and countering immune-defeating properties like hypoxia and acidosis, DCs may induce superior anti-tumor immunity. Despite challenges, the renewed interest in DC vaccines, inspired by Sipuleucel-T’s success and novel immunomodulatory agents, brings hope for transforming cancer treatment.
One approach by which tumor angiogenesis may be disrupted is through the administration of a dendritic cell (DC) vaccine targeting tumor-derived blood vessels, leading to cytotoxic immune responses that decrease tumor growth and synergize with other systemic therapies. Early generations of such vaccines exhibited protection against various forms of cancer in pre-clinical models, but clinical results have historically been disappointing. The unparalleled success of Sipuleucel-T has helped revitalize the clinical development of dendritic cell vaccines, which will be examined in this review.
Tumor-derived blood vessels may serve to inhibit the collective effects of DC vaccines. Sustained tumor-produced VEGF can mediate detrimental effects to DC function through mechanisms that include inducing PD-L1 expression on myeloid DCs, impairing mature DC mobility, and suppressing expression of MHC class II and other costimulatory molecules. Although anti-angiogenic agents such as VEGF-specific antibodies (e.g., bevacizumab) and small molecule drugs (e.g., axitinib, dasatinib, sunitinib) have been approved for some time, resistance to these monotherapies develops quickly in patients due to tumor blood vessels
adopting compensatory reliance on other growth factors. Yet, VEGF blockade in combination with other drugs such as chemotherapy, ICIs, or mTOR inhibitors have shown improved anti-tumor effects. Ultimately, while DC vaccines alone may have a limited ability to catalyze T cell infiltration and immune cell cytotoxicity within the tumor microenvironment based on the aberrant and immunosuppressive properties of the tumor lesion vascular normalization strategies could help unleash the ability of DCs to induce superior anti-tumor immunity by restoring blood flow dynamics and minimizing immune-defeating properties like hypoxia, acidosis, and downregulation of leukocyte adhesion molecules.
Despite the number of mCRC treatments coming to market over the last two decades, the disease still remains deadly in its later stages. DC vaccines have historically performed poorly in clinical trials for cancer, but renewed interest in this immunotherapeutic strategy has been sparked by the relative success of Sipuleucel-T for prostate cancer and advent of immunomodulatory agents that may synergistically improve DC function.
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