Molecular insights into the development of T cell-based immunotherapy for prostate cancer

Abstract

Using a patient’s own immune system to fight cancer is a highly active area of cancer research. Four years ago, sipuleucel-T became the first approved cancer vaccine, which was developed to enhance T-cell immunity against metastatic castration-resistant prostate cancer. Other prostate cancer vaccines, including a viral-based vaccine PROSTVAC-VF and a cellular vaccine GVAX, are in development. Moreover, several clinical trials are investigating the role of immune checkpoint blockade in the treatment of prostate cancer. Ipilimumab and nivolumab are potent T cell checkpoint inhibitors that reverse immunologic tolerance in multiple types of cancers. Here we discuss the mechanisms underlying antitumor T cell responses as well as the development of immunotherapies for prostate cancer.

Keywords::

• cancer vaccine
• immune checkpoint
• immunotherapy
• prostate cancer
• sipuleucel-T
• T cells

Financial & competing interests disclosure

This work was supported by American Heart Association Grant 11SDG7690000 and Fondation de la Recherche en Transplantation Grant IIG201101. The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Prostate cancers, as abnormal tissues, contain tumor-associated antigens that can be recognized by human T cells.

• T cells control the quality and quantity of adaptive immune responses and depend on antigen-presenting cells to pick up and present cognate antigens to them.

• T-cell activation leads to increased expression of cytotoxic T-lymphocyte antigen 4, which is an immune checkpoint protein transmitting inhibitory signal to T cells.

• The development of immune checkpoint in tumors may be a consequence of antitumor immunity. IFN-γ produced by infiltrating CD8⁺ T cells induces PD-L1 expression in tumors.

• Prostate cancer vaccine sipuleucel-T contains autologous antigen-presenting cells that are activated ex vivo with a fusion protein linking prostatic acid phosphatase and GM-CSF.

• PROSTVAC-VF is a viral-based vaccine for prostate cancer. PROSTVAC-VF comprises two vectors, both of which contain a modified PSA and three T-cell stimulatory molecules.

• Adoptive T-cell therapy involves the infusion of ex vivo manipulated T cells back into the same patient. T cells are either naturally occurring or engineered with TCR and chimeric antigen receptors.

• Nivolumab combined with ipilimumab induced >80% tumor reduction in 53% of patients with melanoma. Immune-related adverse events were generally reversible.

Notes