Cancer Vaccines: Adjuvant Potency, Importance of Age, Lifestyle, and Treatments

Abstract

Although the discovery and characterization of multiple tumor antigens have sparked the development of many antigen/derived cancer vaccines, many are poorly immunogenic and thus, lack clinical efficacy. Adjuvants are therefore incorporated into vaccine formulations to trigger strong and long-lasting immune responses. Adjuvants have generally been classified into two categories: those that 'depot' antigens (e.g. mineral salts such as aluminum hydroxide, emulsions, liposomes) and those that act as immunostimulants (Toll Like Receptor agonists, saponins, cytokines). In addition, several novel technologies using vector-based delivery of antigens have been used. Unfortunately, the immune system declines with age, a phenomenon known as immunosenescence, and this is characterized by functional changes in both innate and adaptive cellular immunity systems as well as in lymph node architecture. While many of the immune functions decline over time, others paradoxically increase. Indeed, aging is known to be associated with a low level of chronic inflammation-inflamm-aging. Given that the median age of cancer diagnosis is 66 years and that immunotherapeutic interventions such as cancer vaccines are currently given in combination with or after other forms of treatments which themselves have immune-modulating potential such as surgery, chemotherapy and radiotherapy, the choice of adjuvants requires careful consideration in order to achieve the maximum immune response in a compromised environment. In addition, more clinical trials need to be performed to carefully assess how less conventional form of immune adjuvants, such as exercise, diet and psychological care which have all be shown to influence immune responses can be incorporated to improve the efficacy of cancer vaccines. In this review, adjuvants will be discussed with respect to the above-mentioned important elements.

Keywords: adjuvant; cancer vaccine; immunosenescence; immunotherapy; inflamm-aging; microbiota.

Figure 1

Open cancer vaccine trials. Cancer vaccine trials listed as open at ClinicalTrials.gov on August 2020. The number of trials for each cancer type (A) and for each vaccine type (B) are shown in the bar graph subdivided into phase I, II, and III/IV. Viral vector vaccines include adenovirus and poxvirus, but also trials using yeast-loaded antigens and one using Salmonella-loaded antigens. Cancers with less than 5 open clinical trials are not shown. “In situ vaccinations” (intralesional injection of immune- modulatory molecules) are not included in these graphs. HPV, Human Papilloma Virus; CRC, colorectal cancer; VLP, virus like particle.

Figure 2

Adjuvants and combinatorial immunomodulatory therapies being used in cancer vaccine trials. Cancer vaccine trials listed as open at ClinicalTrials.gov on August 2020. The number of trials using each adjuvant (A) and associating each immunomodulatory therapy with the cancer vaccine (B) are shown in the bar graph. Adjuvants and combinatorial therapies used in less than 2 clinical trials are not shown. GM-CSF, Granulocyte-macrophage colony-stimulating factor; IL-2, interleukin-2; Td, Tetanus/diphtheria toxoid; HSP, heat shock protein; CAF09b, cationic liposomes (DDA-MMG1) with complex bound synthetic double-stranded RNA (Poly(I:C)2); IL-12, Interleukin- 12; P64k, Neisseria meningitides protein; PD-1, Programmed cell death 1; PD-L1, Programmed cell death ligand 1; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; RT, radiotherapy; M7824, fusion protein composed of a human IgG1 monoclonal antibody against PD-L1 fused with 2 extracellular domains of TGF-βRII; IFNalfa, Interferon alfa; IDO1, indoleamine 2,3-dioxygenase 1; ALT-803, IL-15 superagonist; Other vaccines, Salmonella, pneumococcal vaccines; HSC, hematopoietic stem cells.

Figure 3

Improving the efficacy of cancer vaccines: Combinational approaches.