Cancer vaccines in the immunotherapy era: Rational approach

Abstract

The 13th annual World Vaccine Congress held in Washington DC (April 16–18, 2013) sponsored a plenary and a session focused on cancer vaccine. The cancer vaccine session consisted of three presentations: “Cancer vaccine landscape overview” by Dr Jeffrey Schlom, a Chief of the Laboratory of Tumor Immunology and Biology, Center for Cancer Research (CCR), National Cancer Institute (NCI); “Immune-system based cancer vaccines” by Dr Geert-Jan Boons, the Complex Carbohydrate Research Center of the University of Georgia; “Peptide vaccine for malignant gliomas” by Dr Robert Fenstermaker, Chair of the Department of Neurosurgery at Roswell Park Cancer Institute.

As Dr Jay Berzofsky, Chief of the new Vaccine Branch (CCR, NCI) pointed out in the plenary, not only the quantity but also the quality (avidity and longevity)¹ of T cell activation is important for the clearance of cancer cells, each of the presented cancer vaccine platforms will first be reviewed by its immunological design to promote the activation of T cells. Then, the benefits of combined cancer vaccines therapy with conventional cancer therapy will be discussed with a mathematical model from NCI prostate cancer trials.

Keywords: :

• cancer vaccine
• vaccine congress
• tumor associated antigen
• immunology
• combination therapy

Vaccine Platform—Antigens, Adjuvants and Delivery Systems

Dr. Schlom discussed the clinical results from PROSTVAC using poxviral vectors as vaccine delivery platforms which have several advantages; does not replicate, does not integrate into host DNA, can efficiently infect antigen presenting cells, and can insert multiple transgenes. PROSTVAC contains 4 genes encoding prostate-specific antigen and three co-stimulatory molecules (TRICOM), B7–1, ICAM-1, and LFA3, each of which binds to CD28/CTLA4, LFA-1, and CD2 respectively to induce synergistic T cell activation. A randomized multicenter placebo-controlled vaccine therapy trial in castrate-resistant metastatic prostate cancer patients showed 8.5 mo median survival benefit (p = 0.006) and 44% reduction in death rate in vaccine arm.

Dr Fenstermaker presented SurVaxM, a survivin vaccine for malignant glioma. SurVaxM contains an altered peptide antigen by C57M mutation on 53–67 peptides of survivin, a tumor associated antigen. The vaccine is designed to provide increased complex association time and increased peptide presentation to potentially auto-reactive T cell repertoire previously having weak affinity interaction between T cell receptors and major histocompatibility molecules, resulting in a cross-reactive immune response to the wild type peptide. SurVaxM, when injected with Montanide ISA 51 and GM-CSF, induced immunologic effects such as tetramer reactivity in phase I clinical trial in recurrent or progressive malignant gliomas after standard therapy.

Dr. Boons introduced next generation tripartite cancer vaccine composed of Toll like receptor 2 agonist, T helper epitope and aberrantly glycosylated (αGalNAc) MUC1 epitope. The tripartite vaccine is incorporated into phospholipid-based small unilamellar vesicles for delivery. Because aberrantly glycosylated MUC1 protein is expressed on the surface of cancer cells and thought to be a target for antibody-dependent cell-mediated cytotoxicity, the vaccine is designed to elicit not only cellular but also humoral immunity. In a mouse model of mammary tumor, the therapeutic effect of the vaccine was evident primarily due to both its built-in adjuvant and specific antigenic properties.

Combination Therapy

Despite numerous clinical trials and animal studies, only one cancer vaccine has been approved by FDA so far, mainly due to a lack of efficacy.² To reach the required efficacy, one approach is to maximize the intended immune response by designing vaccines to possess multiple functions from specific antigenicity to adjuvant as all the presented vaccines in this section. However, lessons from recent clinical trials seem now to be enough to suggest a new strategy, combination of cancer vaccines with standard therapy. Dr Schlom presented a very interesting mathematical model showing the benefits of the combination therapy derived from NCI prostate cancer trials over the last decade. In this model, although the vaccine alone appears not to provide any therapeutic efficacy, however, when it was combined with cytotoxic therapy, it may improve time to progression with continued immune responses after vaccination. If this model is validated by other clinical studies, the tumor growth rate can be a new clinical endpoint which fills the gap between time to progression and death rate.³ Further researches should be focused on the evaluation of specific drugs or therapies making tumors susceptible to cancer vaccine-mediated immune responses and the clinical designs facilitating combination therapy. Most of all, minimal toxicity of cancer vaccine is essential.

Conclusion

Critical factors for future success will be cancer specific antigen combined with adjuvant to elicit appropriate/prolonged immune response, efficient delivery, and more importantly, clinical trial design to correctly evaluate vaccine efficacy. Combination therapy with other active or passive immunotherapy as well as conventional cancer therapy is desirable if it is precisely designed to maximize the therapeutic efficacy.

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.