Abstract
Simple SummaryThe only vaccine approved by FDA as a treatment for cancer is sipuleucel-T, a therapy for patients with metastatic castration-resistant prostate cancer (mCRPC). Most investigators studying anti-tumor vaccines believe they will be most effective as parts of combination therapies, rather than used alone. Unfortunately, the cost and complexity of sipuleucel-T makes it difficult to feasibly be used in combination with many other agents. In this review article we discuss the use of DNA vaccines as a simpler vaccine approach that has demonstrated efficacy in several animal species. We discuss the use of DNA vaccines in combination with traditional treatments for mCRPC, and other immune-modulating treatments, in preclinical and early clinical trials for patients with mCRPC.Metastatic castration-resistant prostate cancer (mCRPC) is a challenging disease to treat, with poor outcomes for patients. One antitumor vaccine, sipuleucel-T, has been approved as a treatment for mCRPC. DNA vaccines are another form of immunotherapy under investigation. DNA immunizations elicit antigen-specific T cells that cause tumor cell lysis, which should translate to meaningful clinical responses. They are easily amenable to design alterations, scalable for large-scale manufacturing, and thermo-stable for easy transport and distribution. Hence, they offer advantages over other vaccine formulations. However, clinical trials with DNA vaccines as a monotherapy have shown only modest clinical effects against tumors. Standard therapies for CRPC including androgen-targeted therapies, radiation therapy and chemotherapy all have immunomodulatory effects, which combined with immunotherapies such as DNA vaccines, could potentially improve treatment. In addition, many investigational drugs are being developed which can augment antitumor immunity, and together with DNA vaccines can further enhance antitumor responses in preclinical models. We reviewed the literature available prior to July 2020 exploring the use of DNA vaccines in the treatment of prostate cancer. We also examined various approved and experimental therapies that could be combined with DNA vaccines to potentially improve their antitumor efficacy as treatments for mCRPC.
Highlights
Prostate cancer has been generally viewed as an immunologically “cold” tumor, because trials evaluating T-cell checkpoint blockade therapies, including anti-PD-1 or anti-CTLA-4, have shown little benefit for all but a small number of patients with prostate cancer [1,2,3,4]
With the goal of augmenting the efficacy of DNA vaccines in controlling prostate tumor growth, this review explores DNA vaccine combinations under investigation with current therapies for metastatic castration-resistant prostate cancer, as well as immunomodulatory agents (immune checkpoint blockade, Toll-like receptors (TLR) ligands, and indoleamine 2,3 dioxygenase (IDO) inhibitors)
Androgen deprivation in patients with biochemically recurrent prostate cancer at high risk of metastasis, patients who received Sip-T followed by Androgen deprivation therapy (ADT) had increased IFN-γ responses to PA2024 compared to patients treated with ADT followed by Sip-T at the 6 week time point and increased PA2024-specific T cell proliferation averaged over all time points [66]
Summary
Prostate cancer has been generally viewed as an immunologically “cold” tumor (i.e., devoid of infiltrating lymphocytes), because trials evaluating T-cell checkpoint blockade therapies, including anti-PD-1 or anti-CTLA-4, have shown little benefit for all but a small number of patients with prostate cancer [1,2,3,4]. Patients with newly diagnosed prostate cancer who were treated with Sip-T prior to prostatectomy had significantly more tumor-infiltrating T cells [21] This suggests that agents, such as T-cell checkpoint molecules that can modulate the function of these tumor-infiltrating lymphocytes, might best be combined with antitumor vaccines. This approach was tested in a murine model of prostate cancer, in which TRAMP mice were treated with the cellular vaccine. Decreased tumor grade and increased lymphocytic infiltration of tumors was observed only with the combination treatment [22] This combination was evaluated in a small clinical trial in which patients with advanced prostate cancer were treated with the GVAX vaccine in combination with ipilimumab [23]. Combining DNA vaccines with other therapies is a valid approach for the treatment of mCRPC, and these combinations will be the focus of this review
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