Therapeutic cancer vaccines: A new treatment modality or a dead end?

July 2021 Clinical Practice Tobias Rawson

Despite the successful vaccination against hepatitis B (HBV) and human papillomavirus (HPV), which are known to cause liver and cervical cancer, respectively, the efficacy of cancer vaccines has been problematic.1,2 Unlike these aforementioned vaccines, cancer vaccines are therapeutic, as opposed to prophylactic, and face three major challenges: (1) historical cancer vaccines typically have a low immunogenicity; (2) tumour mutational burden can ‘out-pace’ and evade the adaptive immune response induced by a vaccine; (3) the tumour microenvironment can be immunosuppressive. Despite these hurdles, the advent of checkpoint inhibitors (CPIs) may provide a means by which tumour mutational pathways can be halted, increasing the efficacy of a vaccine-associated adaptive immune response. Activation of both CD4 and CD8 T cells requires the receptor binding of multiple pathways, and combining the stimulants of these receptors with cancer vaccines also has the potential to propagate a clinically meaningful immune response. Furthermore, the low immunogenicity observed in previous cancer vaccine clinical trials may be due to these vaccines using tumour-associated antigens (TAAs), which although are expressed to a high degree on cancer cells, are not tumour-specific and can be found on healthy cells as well. Self-recognising T-cells are predominantly eliminated during development, which can further lower a vaccines immunogenicity. With this knowledge, vaccine research has improved in recent years, utilising more specific antigens, better vectors and efficacious co-stimulants. These advancements, as well as historical limitations, will be discussed in this review. 3-5

Cancer vaccine antigens

The ideal cancer vaccine would present an antigen to the immune system that is expressed exclusively by cancer cells, and is essential to tumour survival. Additionally, this antigen would be highly immunogenic, inducing the clonal expansion of both CD4+ and CD8+ T cells up to, and past, the concentration threshold needed to result in a high degree of efficacy. Achieving all three of these criteria has proven difficult, although advancements in antigen design has resulted in an increase in efficacy in recent years.

Tumour-associated antigens

Historically, the majority of cancer vaccines have utilised TAAs, which although are overexpressed on cancer cells, are not specific to a tumour, and can be found on the surface of healthy cells as well. This presents several challenges. Firstly, given that these are self-antigens, B cells and T cells that recognise these antigens are largely eliminated from the immune cell reservoir via central and peripheral tolerance. As a result, vaccines that utilise TAAs are stimulating immune cells that are found in very low concentrations. Too low, potentially, to induce a clinically meaningful response. Despite attempts to amplify response via co-stimulators and booster vaccinations, a response to TAA-utilising vaccines is often seen as stimulating an antigen-specific CD8 T cell population to a level of <1% of the total circulating CD8 T cells. In contrast, the YF-Vax yellow fever and Dryvax smallbox vaccines stimulate clonal expansion of CD8 T cells to 12.5% and 40% of total peripheral CD8 T cells, respectively.6-8 Additionally, immune responses to TAAs can result in collateral damage due to their expression on normal cells. Such is the case with CAR-T cell therapy against the CEA antigen for colorectal cancer, which can result in severe colitis as CEA is expressed on healthy intestinal tissue. 9

Tumour-specific antigens (neoantigens)

In contrast to TAAs, antigens that arise from oncogenic mutation are recognised as foreign by the immune system and are highly immunogenic. Although some common neoantigens have been identified between different cancers, the majority of these antigens are unique and specific to an individual’s own tumour. As a result, the production of a cancer vaccine that utilises neoantigens is a personalised, multi-step process; the patients tumour genome is sequenced, mutations are identified and neoantigens are then predicted in silico using machine learning. With these antigens identified, a vaccine containing these predicted neoantigens is then produced and delivered to the patient. Two phase I studies have utilised this approach in melanoma patients with encouraging results. One study of 13 stage III-IV melanoma patients who received a multi-neoantigen RNA-based vaccine found that 8 patients remained recurrence-free for up to 23 months (the maximum follow-up period). The remaining 5 patients experienced relapses shortly after enrolment, although one patient developed an objective clinical response, with another developing a complete response in multiple progressing metastatic lesions when combined with CPIs, and remained relapse-free for 26 months. 10 Ott et al., also demonstrated the efficacy of a personalised neoantigen vaccine in 6 melanoma patients, finding that 4 of these patients were without recurrence at 25 months post-vaccination, and that the remaining 2 who did progress experienced complete tumour regression when treated with anti-PD-1 therapy. 11 These two studies clearly demonstrate a preliminary efficacy with neoantigen cancer vaccines, as well as demonstrating a potential synergistic action with CPIs. However, promising results in early-phase settings have been observed with other cancer vaccine modalities, only to be found ineffective in later phases. Additionally, the development of a personalised, neoantigen vaccine involves a lengthy production process, by which point the patient may have progressed or developed immune evasion mechanisms. It is also a costly process, as an individual’s tumour has to be sequenced in full. Until this process becomes cheaper, this will inevitably price out some patients, and patients of lower-income countries. Finally, the identification and selection of neoantigens relies on mutational burden, which varies between different cancer types. Cancers that have a higher mutational burden have more neoantigens, increasing the chances of an effective therapeutic vaccine. 12

Cancer vaccine vectors

The lack of efficacy from previous cancer vaccine attempts has identified T-cell response as the main effector of therapeutic vaccines. In contrast, prophylactic vaccines aim to induce deep B-cell responses. Current research now focuses on the development of three types of cancer vaccine vector: cellular vaccines, viral vector vaccines and molecular vaccines, which contain either small peptides, DNA or RNA.13-16

Cellular vaccines

Cellular therapies have in fact been used for many years. Perhaps the most well-known, is Bacillus Calmette-Guerin (BCG), which is used to treat non-muscle-invasive bladder cancer. 17 In theory, bacteria can be used as vectors for the delivery of DNA- or RNA-encoded tumour antigens, which are taken up by antigen presenting cells, such as dendritic cells (DCs). 18 However in practice, conversion of early-phase efficacy to later phase trials has not been easy. Such is the case in advanced pancreatic cancer, which saw promising phase II data with a vaccine containing Listeria-expressing mesothelin (CRS-207), only for these results not to be replicated in a larger phase IIb study. 19, 20 Irradiated allogeneic or autologous tumour cell lines have also been used as vaccine vectors. Vaccines such as these benefit from inactive whole tumour cells, which come complete with presentable neoantigens. As a result, the major advantage with this modality is that neoantigens no longer have to be identified and processed. Unfortunately however, these too have seen limited success, offering only moderate efficacy at best in prostate, lung, and pancreatic cancers, as well as melanoma, despite stimulating immune responses. 21-24 Finally, cellular vaccines containing autologous DCs which have been primed to present neoantigens have been studied extensively. 25 Furthermore, the FDA has approved a DC-based cancer vaccine, sipuleucel-T, for use in metastatic castration-resistant prostate cancer (mCRPC). Approval came following the results of the phase III IMPACT trial, which randomised (2:1) 512 mCRPC patients to receive sipuleucel-T or placebo. A modest, but significant improvement in median overall survival (OS) was observed with the vaccine (25.8 months vs. 21.7 months; HR[95%CI]: 0.78[0.61-0.98], P= 0.03). 26  Unfortunately, sipuleucel-T suffers from the timely complexity of production and cost, limiting its widespread use.

Peptide vaccines

Previously, research into peptide vaccines have utilised short peptides. Less than 15 amino acids long, these peptides do not need to be processed by APCs to effectively bind with major histocompatibility complexes (MHCs). However, without APC presentation, direct binding of peptides to MHCs results in tolerogenic signalling and T cell dysfunction. Crucially however, short peptides do not elicit a CD4+ T cell response, which is essential for the full activation and expansion of CD8 cytotoxic T cells. 27, 28 More recently, synthetic long peptides (SLPs) have demonstrated the induction of both CD8 and CD4 T cell responses through the dual presentation of epitopes on both class 1 and class 2 MHCs. 29

Viral vector vaccines

The human immune system is well adapted to react to a viral infection. As a result, viral vector vaccines are able to elicit both an innate and adaptive immune response via the recognition of viral pathogen-associated molecular patterns by APCs. However, this immune response can often neutralise this viral vector, limiting both the efficacy of the initial vaccine, and any repeat vaccination thereafter. To overcome this, a heterologous prime-boost strategy has been investigated, whereby two different viral vectors are used, administered as a primary and booster vaccine. Unfortunately, this approach also appears to have inconclusive efficacy between phase II and III settings. In 2017, the PROSTVAC-VF vaccine, which was comprised of a vaccinia-based primary and six fowlpox-based boosters was found to induce a statistically significant improvement in median overall survival in 125 men with mCRPC (26.2 months vs. 16.3 months; HR[95%CI]: 0.4997[0.3201-0.7801], P= 0.0019). 30 Conversely, the evaluation of this vaccine was stopped early in a phase III setting, after an interim analysis found it was unlikely to improve OS compared to placebo. 31 In light of these results, a vaccine-based immunotherapy regimen (VBIR) has been constructed, incorporating CTLA-4 and PD-1 CPIs to boost T cell priming and prolong activity. 32 This is currently being evaluated in a phase I setting. 33      

DNA and RNA Vaccines

Similar the peptide vaccines, DNA and RNA vaccines are structurally simple and are able to induce DC activation without the need for a signal-boosting adjuvant. Furthermore, they do not provoke a strong anti-vector response, allowing for repeated dosing. Despite this, uptake efficiency by immune cells is low, and techniques to improve uptake have been investigated. Delivery via microneedle arrays, gene gun, nanoparticles, and electroporation have all been found to improve transfection. 34 Such vaccines have found particular efficacy in cervical cancer, with a phase IIb trial of 167 women with grade 2/3 cervical intraepithelial neoplasia (CIN) demonstrating significant tumour regression in 49.5% who received the DNA vaccine VGX-3100 (N= 107), compared to 30.6% who received a placebo (N= 42) (P= 0.034). 35 Additionally, RNA vaccines may be more efficacious, as they do not need to pass through the nuclear membrane, unlike DNA vaccines. Although RNA vaccines are more susceptible to degradation via RNases, their half-life can be prolonged by modifying their chemical structure. 36

Therapy combinations

To evade immunosurveillance, cancers often employ several oncogenic and immunosuppressive pathways at once. In recent years, CPIs have transformed the treatment paradigm for many cancers, and preclinical studies have demonstrated the synergy between CPIs and therapeutic cancer vaccines. 37 More recently, a phase II study offered encouraging data with a CPI-vaccine combination, finding an overall response rate of 33% in 24 patients with incurable HPV-16-positive cancer, when given the long-peptide ISA101 vaccine in combination with nivolumab. 38 Unfortunately, not all CPI-vaccine combinations have been fruitful. In a phase III study by Hodi et al., the addition of the short peptide gp100 vaccine to ipilimumab did not improve survival outcomes in melanoma patients. 39 As previously mentioned, an optimal immune response relies on both activation of CD4+ and CD8+ T cells. Neoantigen presentation via APCs is not enough to elicit a full signalling cascade, and co-stimulators are required to activate CD8 cytotoxic T cells. Normally, these costimulators are received from APCs, particularly DCs, as well as from CD4 T helper cells. With this in mind, co-stimulators can be combined, in theory, with cancer vaccines to further propagate a T cell response. Studies in mice have confirmed this synergy, showing that OX40 antibodies enhanced CD4 and CD8 T cell responses in mice models. 40, 41 Taking this approach further, triple combinations of vaccines, CPIs and costimulators have also been investigated. An adenoviral vaccination in combination with anti-CD40 and anti-CTLA-4 monoclonal antibodies was able to induce complete regression and long-term survival in 30-40% of mice. 42  In another mice study, when combined with a HER2-directed therapeutic vaccine, OX40 agonism and CTLA-4 blockade induced robust CD4 and CD8 T cell responses, as well as extensive tumour destruction and T-cell infiltration. 43 Interleukin-2 (IL-2) is a key co-stimulator of cytotoxic T cells, and has also been investigated as a potential cancer vaccine adjuvant. In an encouraging development, a gp100-like vaccine was found to significantly improve progression-free survival when combined with IL-2, compared to IL-2 alone in 185 patients with stage III or IV melanoma in a phase III trial (2.2 months vs. 1.6 months; P= 0.008), as well as numerically improve median overall survival (25.8 months vs. 11.1 months; P= 0.06). 44

Lastly, chemo/radiotherapy-vaccine combinations have also been investigated. In particular, radiotherapy has been shown to induce immunogenic tumour cell stress, resulting in enhanced T cell response and synergy with cancer vaccines. 45, 46 This is a relatively new area of research that is still being developed. 47 The synergistic relationship between chemotherapy and cancer vaccines is also well documented. 48 Perhaps the most compelling evidence of this relationship comes from a phase IIb study, which found that TG4010, an MUC-1- and IL-2-expressing, modified Ankara viral vaccine, was able to induce a longer progression-free survival and a higher rate of confirmed responses when combined with platinum-based chemotherapy, compared to chemotherapy alone (mPFS: 5.9 months vs. 5.1 months; HR[95%CI]: 0.74[0.55-0.98], P= 0.019).


In closing, although historically unremarkable, emerging research around therapeutic vaccines is encouraging. Learning from previous failures, this area of research now has many antigen and vector combinations to explore, with even greater potential efficacy when combined with other co-stimulants and systemic therapies. However, in the majority of cases, this therapy is far from clinical realisation. In the case of cancer vaccines that utilise neoantigens or whole cells, cost and manufacture time are major hurdles that make this treatment unfeasible for many patients. Furthermore, not all patients respond to immunotherapy, and it is likely that cancer vaccines will not be applicable to everyone. Predictive biomarkers will help to personalise this treatment modality in the future and ultimately, more research is required to establish vaccine designs that can significantly impact survival outcomes in a phase III setting.   


  1. Kim BK, Han KH, Ahn SH. Prevention of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. Oncology. 2011; 81(suppl 1): 41-49.
  2. Roden RBS, Stern PL. Opportunities and challenges for human papillomavirus vaccination in cancer. Nat Rev Cancer. 2018; 18(4): 240-254.
  3. Hurez V, Padron AS, Svatek RS et al., Considerations for successful cancer immunotherapy in aged hosts.Clin Exp Immunol. 2017; 187(1): 53-63.
  4. Zitvogel L, Apetoh L, Ghiringhelli F et al., Immunological aspects of cancer chemotherapy. Nat Rev Immunol. 2008; 8(1): 59-73.
  5. Thommen DS, Schumacher TN. T Cell Dysfunction in Cancer. Cancer Cell. 2018; 33(4): 547-562.
  6. Pedersen SR, Sorensen MR, Buus S et al., Comparison of vaccine-induced effector CD8 T cell responses directed against self- and non-self-tumor antigens: implications for cancer immunotherapy. J Immunol. 2013; 191(7): 3955-3967.
  7. Overwijk WJ. Cancer vaccines in the era of checkpoint blockade: the magic is in the adjuvant. Curr Opin Immunol. 2017; 74: 103-109.
  8. Miller JD, van der Most RG, Akondy RS et al., Human effector and memory CD8+ T cell responses to smallpox and yellow fever vaccines. Immunity. 2008; 28(5): 710-722.  
  9. Parkhurst MR, Yang JC, Langan RC et al., T cell targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol Ther. 2011; 19(3): 620-626.
  10. Sahin U, Derhovanessian E, Miller M et al., Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017; 547: 222-226.
  11. OTT PA, Hu Z, Keskin DB et al., An Immunogenic Personal Neoantigen Vaccine for Melanoma Patients. Nature. 2017; 547(7662): 217-221.
  12. Smith CC, Selitsky SR, Chai S et al., Alternative tumour-specific antigens. Nature Rev Cancer. 2019; 19: 465-478.
  13. Kumai T, Fan A, Harabuchi Y et al., Cancer immunotherapy: moving forward with peptide T cell vaccines. Curr Opin Immunol. 2017; 47: 57-63.
  14. Van Der Burg SH, Arens R, Ossendorp F et al., Vaccines for established cacner: overcoming the challenges posed by immune evasion. Nat Rev Cacner. 2016; 16(4): 219-233.
  15. Lee SH, Danishmalik SN, Sin JI. DNA vaccines, electroporation and their applications in cancer treatment. Hum Vaccin Immunother. 2015; 11(8): 1889-1900.
  16. Sahin U, Kariko K, Tureci O. mRNA-based therapeutics- developing a new class of drugs. 2014; 13: 759-780.
  17. Redelman-Sidi G, Glickman MS, Bochner BH. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat Rev Urol. 2014; 11(3): 153-162.
  18. Bolhassani A, Naderi N, Soleymani S. Prospects and progress of Listeria-based cancer vaccines. Expert Opin Biol Ther. 2017; 17(11): 1389-1400.
  19. Le DT, Wang-Gillam A, Picozzi V et al., Safety and survival with GVAX pancreas prime and Listeria Monocytogenes-expressing mesothelin (CRS-207) boost vaccines for metastatic pancreatic cancer. J Clin Oncol. 2015; 33(12): 1325-1333.
  20. Le DT, Picozzi VJ, Ko HA et al., Results from a Phase IIb, randomized, multicenter study of GVAX Pancreas and CRS-207 Compared with Chemotherapy in Adults with Previously Treated Metastatic Pancreatic Adenocarcinoma (ECLIPSE Study). Clin Cancer Res. 2019; 25(18): 5493-5502.
  21. Small EJ, Sacks N, Nemanaitis J, Urba WL et al., Granulocyte macrophage colony-stimulating factor-secreting allogeneic cellular immunotherapy for hormone-refractory prostate cancer. Clin Cancer Res. 2007; 13(13): 3883-3891.
  22. Lipson EJ, Sharfman WH, Chen S et al., Safety and immunologic correlates of Melanoma GVAX, a GM-CSF secreting allogeneic melanoma cell vaccine administered in the adjuvant setting. J Transl Med. 2015; 13: 214.
  23. Laheru D, Lutz E, Burke J et al., Allogeneic granulocyte macrophage colony-stimulating factor-secreting tumor immunotherapy alone or in sequence with cyclophosphamide for metastatic pancreatic cancer: a pilot study of safety, feasibility, and immune activation. Clin Cancer Res. 2008; 14(5): 1455-1463.
  24. Salgia R, Lynch T, Skarin A et al., Vaccination with irradiated autologous tumor cells engineered to secrete granulocyte-macrophage colony-stimulating factor augments antitumor immunity in some patients with metastatic non-small-cell lung carcinoma. J Clin Oncol. 2003; 21(4): 624-630.
  25. Butterfield LH, Santos PM. Dendritic Cell-Based Cancer Vaccines. J Immunol. 2018; 200(2): 443-449.
  26. Kantoff PW, Higano CS, Shore ND et al., Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Eng J Med. 2010; 363(5): 411-422.
  27. Toes RE, Offringa R, Blom RJ et al., Peptide vaccination can lead to enhanced tumor growth through specific T-cell tolerance induction. Proc Natl Acad Sci USA. 1996; 93(15): 7855-7860.
  28. Hailemichael Y, Dai Z, Jaffarzad N et al., Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat Med. 2013; 19(4): 465-472.
  29. Zhang H, Hong H, Li D et al., Comparing pooled peptides with intact protein for accessing cross-presentation pathways for protective CD8+ and CD4+ T cells. J Biol. Chem. 2009; 284(14): 9184-9191.  
  30. Kantoff PW, Gulley JL, Pico-Navarro C. Revised Overall Survival Analysis of a Phase II, Randomized, Double-blind, Controlled Study of PROSTVAC in Men With Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2017; 35(1): 124-125.
  31. Gulley JL, Borre M, Vogelzang NJ et al., Phase III Trial of PROSTVAC in Asymptomatic or Minimally Symptomatic Metastatic Castration-Resistant Prostate Cancer. J Clin Oncol. 2019; 37(13): 1051-1061.
  32. Cho H, Cockle P, Joe B et al., Vaccine based immunotherapy regimen (VBIR) for the treatment of prostate cancer. Cancer Res. 2016; 76(14): LB-093.
  33. A Phase 1 Study To Evaluate Escalating Doses Of A Vaccine-Based Immunotherapy Regimen For Prostate Cancer (PrCa VBIR) [internet]. 2015 [updated March 9th 2021; cited July 29th 2021]. Available from:
  34. Jorritsma SHT, Gowans EJ, Grubor-Bauk B et al., Delivery methods to increase cellular uptake and immunogenicity of DNA vaccines. Vaccine. 2016; 34(46): 5488-5494.
  35. Trimble CL, Morrow MP, Kraynyak KA et al., Safety, Efficacy and immunogenicity of VGX-3100, a therapeutic synthetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7 proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-blind, placebo-controlled phase 2b trial. Lancet. 2015; 386(10008): 2078-2088.
  36. Kariko K, Muramatsu H, Welsh FA et al., Incorporation of pseudouridine in mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. 2008; 16(11): 1833-1840.
  37. Ali OA, Lewin SA, Dranoff G et al., Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication. Cancer Immunol Res. 2016; 4(2): 95-100.
  38. Massarelli M, William W, Johnson F et al., Combining Immune Checkpoint Blockade and Tumor-Specific Vaccine for Patients With Incurable Human Papillomavirus 16-Related Cancer. JAMA Oncol. 2019; 5(1): 67-73.
  39. Hodi SF, O’day SJ, McDermott DF et al., Improved survival with Ipilinmumab in Patients with Metastatic Melanoma. New Eng J Med. 2010; 363: 711-723.
  40. De Smedt T, Smith J, Baum P et al., Ox40 Costimulation Enhances the Development of T Cell Responses Induced by Dendritic Cells In Vivo. J Immunol. 2002; 168(2): 661-670.
  41. Murata S, Ladle BH, Kim PS et al., OX40 costimulation synergizes with GM-CSF whole-cell vaccination to overcome established CD8+ T cell tolerance to an endogenous tumour antigen. J Immunol. 2006; 176(2): 974-983.
  42. Sorensen MR, Holst PJ, Steffensen MA et al., Adenoviral vaccination combined with CD40 stimulation and CTLA-4 blockage can lead to complete tumor regression in murine melanoma model. Vaccine. 2010; 28(41): 6757-6764.
  43. Linch SN, Kasiewicz MJ, McNamara MJ et al., Combination OX40 agonism/CTLA-4 blockade with HER2 vaccination reverses T-cell anergy and promotes survival in tumor-bearing mice. Proc Natl Acad Sci USA. 2016; 133(3): E319-E327.
  44. Schwartzentruber DJ, Lawson DH, Richards JM et al., gp100 Peptide Vaccine and Interleukin-2 in Patients with Advanced Melanoma. New Eng J Med. 2011; 364: 2119-2127.
  45. Ferrara TA, Hodge JW, Gulley JL. Combining radiation and immunotherapy for synergistic antitumor therapy. Curr Opin Mol Ther. 2009; 11(1): 37-42.
  46. Gameiro SR, Jammeh ML, Wattenerg MM et al., Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget. 2014; 5(2): 403-416.
  47. Cadena A, Cushman TR, Anderson C et al., Radiation and Anti-Cancer Vaccines: A Winning Combination. Vaccines. 2018; 6(1): 9.
  48. Gatti-Mays ME, Redman JM, Collins JM et al., Cacner vaccines: Enhanced immunogenic modulation through therapeutic combinations. Hum Vaccin Immunother. 2017; 13(11): 2561-2574.
  49. Quoix E, Lena H, Losonczy G et al., TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016; 17(2): 212-223.