Could mycobacterial Hsp70-containing fusion protein lead the way to an affordable therapeutic cancer vaccine?

Abstract

Cancer vaccine development efforts have recently gained momentum, but most vaccines showing clinical impact in human trials tend to be based on technology approaches that are very costly and difficult to produce at scale. With the projected doubling of the incidence of cancer and its related cost of care in the U.S. over the next two decades, the widespread clinical use of such vaccines will prove difficult to justify. Heat shock protein-based vaccines have shown the potential to elicit clinically meaningful immunologic responses in cancer, but the predominant development approach – heat shock protein–peptide complexes derived from a patient’s own tumor – face similar challenges of cost and scalability. New innovative modalities for deploying heat shock proteins in cancer vaccines may open the door to vaccines that can generate potent cytotoxic responses against multiple tumor targets and can be made in a cost-effective and scalable manner.

Keywords:

• antigen presenting cells
• cancer treatment costs
• cancer vaccine
• heat shock protein
• immunotherapy
• mesothelioma
• ovarian cancer
• tumor associated antigens

Acknowledgements

This manuscript is dedicated to the memory of Janet Gelfand, a victim of ovarian cancer. The authors gratefully acknowledge the support that allowed for the original research discussed in this manuscript to be performed: The Edmund C. Lynch Jr. Cancer Fund, Arthur Luxenberg Esq., Perry Weitz Esq., and the Friends of VIC Fund.

Financial & competing interests disclosure

Gelfand is an inventor of a number of patents related to the heat shock protein–antibody fusion protein, which are assigned to Massachusetts General Hospital, of which all authors are employees. The authors have no other 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.

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

Key issues

• There is renewed interest in the cancer vaccine market with the first US FDA-approved cancer vaccine, Provenge, and the encouraging clinical results of a new class of systemic immunomodulators such as immune checkpoint blockade biologicals.

• The key to effective therapeutic vaccines for cancer is the induction of potent CD8⁺ T-cell responses and the promotion of T-cell memory against tumor-associated antigens.

• In general, vaccines that utilize standardized protein, peptide or nucleotide platforms are scalable and economic from the perspective of production, but limited in their potency due to the use of a limited range and type of tumor-associated antigen (TAA) and the difficulty of inducing significant CD8⁺ T-cell responses.

• Vaccines that rely on more personalized, customized approaches such as tumor cell vaccines or dendritic cell vaccines are capable of presenting a broader range of TAAs to the immune system and inducing significant CD8⁺ T-cell response, but are expensive to produce and difficult to manufacture in a scalable manner.

• The challenge of producing effective cancer vaccines will become more acute with the anticipated doubling of the number of cancers diagnosed each year over the next 15 years. The health care system will not be able to absorb a series of highly expensive treatment approaches.

• Heat-shock proteins (HSPs), which have multifactorial effects on both the innate and adaptive immune system, may offer a way to address this dilemma as they are capable of generating significant CD8⁺ T-cell responses against tumors. However, current uses of HSPs in vaccines fall into the current paradigm of either presenting a limited range of TAAs or requiring complex and expensive customized vaccine production.

• HSPs in combination with tumor-targeting molecules have the potential to escape this dilemma. Such protein fusions target HSPs to the tumor tissue, where HSPs can bind to local antigen-presenting cells, stimulating cytokine release, tumor uptake and cross-presentation of a range of tumor antigens and maturation of dendritic cells, which together significantly enhances CD8⁺ T-cell responses against multiple tumor antigens.

• This new approach requires further development to optimize parameters of treatment, and it may benefit from combination with systemic immunomodulatory therapy, but it can be applied to multiple types of cancers.

Notes