Therapeutic cancer vaccines: a long and winding road to success

Abstract

Harnessing the immune system to achieve therapeutic efficacy in cancer has been a milestone in immuno-oncology. Tumor-induced suppression works as an obstacle for the effectiveness of immunotherapies. Advances in our understanding of the interrelationship between cancer immunoediting and immunotherapy led to successful manipulation of anticancer immunity; this provided the platform for combining cancer vaccines with chemotherapies counteracting, to some extent, tumor-induced suppressive entities and demonstrating clinical efficacy. Targeting co-inhibitory and co-stimulatory receptors with immunostimulatory antibodies has also shown clinical promise and its combined use with vaccines is a promising new approach of immunotherapy for cancer. Recent evidence supporting vaccine administration in patients with early and less aggressive disease should be additionally placed to select the appropriate patient population and to identify earlier markers of clinical benefit and immunological parameters that correlate with survival. This review focuses on promising vaccination platforms and essential perspectives in the treatment of cancer.

Keywords::

• biomarkers
• cancer immunotherapy
• chemotherapy
• immunostimulatory antibodies
• small molecule inhibitors
• vaccines

Financial & competing interests disclosure

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

• The theory of ‘cancer immunoediting’ has paved the way for applying cancer immunotherapies aiming at the enhancement of immune surveillance and blocking of tumor-induced immune suppression.

• It is preferable that therapeutic cancer vaccines include both cytotoxic T lymphocytes (CTL) and T helper cell epitopes, so to induce robust antitumor immunity. Dendritic cells and pox viral vectors are commonly used as vaccine vehicles.

• Chemical linkage of an invariant chain epitope (Ii-key) to helper peptides renders them more immunogenic than the native peptides. Ii-key hybrid peptide vaccines have shown so far great promise in clinical trials with breast and prostate cancer patients.

• Ongoing Phase II clinical trials combine vaccination with chemotherapies. In addition, there are preclinical studies and Phase I/II trials to show the synergism between vaccines and monoclonal antibodies or small molecule inhibitors.

• Potential optimal clinical design should include patients at the earlier stages of disease, or in the adjuvant setting or, when in the metastatic setting, patients should have indolent disease.

• Vaccines should induce tumor-specific CD8+ cytotoxic T lymphocytes of high avidity, immunological memory and, in the presence of tumor burden, epitope-spreading.

• Combinatorial treatments (vaccines plus chemotherapy, immunostimulatory monoclonal antibodies (mab) and small molecule inhibitors) are clearly needed.

• The functional status of Tregs should be precisely defined before applying Treg-depleting protocols.

• Indoleamine 2,3-dioxygenase activity should be further explored as a predictor of immune system activation.

Notes