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Cancer Vaccines: Is Success Around the Corner or Several Decades Away (Again)?
 

 

Is there any anti-cancer modality that has seen as much effort with so little results as cancer vaccines? The history of cancer vaccines over the last 40 years reveals enormous investment of scientific and clinical resources. Attempts to create effective vaccines have extended across all types of cancer, from hematological malignancies to solid tumors. Lymphoma offers a particularly attractive setting since the transformed B cells produce a unique B cell receptor protein or idiotype, which can be used to make a patient specific vaccine. Idiotype vaccines from Genitope and Favrille progressed to large, randomized Phase III trials which did not demonstrate survival benefit.1,2 In these products, the patient's variable region was inserted for convenience into an IgG without regard for the actual isotype of the tumor, perhaps creating a tolerogenic effect. BiovaxID's Dasiprotimut reproduced the patient's entire isotype and progressed to Phase III trials but also failed to gain regulatory approval.3

In lung cancer, vaccines have been tested as adjuvant therapies in the hope of extending survival when added to standard surgical or cytotoxic treatments, treatments whose survival benefit is limited.4,5 The large-scale randomized trials show trends toward increased survival, and when subgroups (sometimes predefined) are evaluated, the improvement in survival is statistically significant.16 But ultimately, these trials do not establish benefit. With the exception of the controversial dendritic prostate cancer cell vaccine Provenge and the atypical HPV vaccine Gardasil, no vaccines have been approved.

Given the huge investment, a legitimate question might be, why is this? Is it because we have not used the right vaccines in the right cancer? Have the vaccines been well designed? Alternatively, perhaps cancer vaccines are doomed to never really add clinical benefit. In this short analysis, we will explore these questions, describe some lessons learned, and proffer some tentative predictions.

One of the powerful attractions of cancer vaccines is their excellent safety profile. Compared to even highly specific, targeted drugs, such as the small molecule EGFR tyrosine kinase inhibitor erlotinib, cancer vaccines tend to have exceptionally benign side effects. While erlotinib can cause serious rash, the most common problem with cancer vaccines tends to be injection site reactions.6 Thus, if cancer vaccines can achieve efficacy, it is hard to imagine anti-cancer agents that will be better tolerated. This feature of cancer vaccines has been a driving and ultimately, justifiable, force.

A second motivation is that the conceptual basis for cancer vaccines is reasonable. Destruction of tumor cells by the immune system is carried out by antigen-specific cytotoxic T cells. These T cells recognize tumor antigens presented by antigen presenting cells. Tumors are genetically unstable, with defects in DNA repair pathways, and thus they generate mutant proteins. In many cases, mutant proteins have been confirmed as tumor antigens by tumor immunologists, that is, T cells with specificity for these antigens have been observed and these T cells suppress tumor growth in preclinical models. Moreover, in some cases, their presence may be associated with better survival in human cancer, with all of the caveats necessary for single arm trials.7

Beyond the recognition of “foreign” tumor antigens, we know that the immune system does not only exclusively respond to nonself, but also responds to danger signals, signals which are released in the form of activating cytokines when tumors form and the normal architecture of a tissue is disrupted. Despite this, skeptics of tumor immunology used to assert that the host would never aggressively fight tumors because the immune system had become tolerant to self-antigens. This argument has not stood up over time. Tolerance can be broken as illustrated by the frequent incidence of autoimmune disease and cancer patients clearly respond to self-antigens. 

Nevertheless, it is widely accepted that self-antigens do not make the best cancer vaccine constituents since T cells with high-avidity TCRs to these proteins have been removed during thymic selection. One of the best examples of the problematic nature of self-antigens comes from a key trial of Ipilimumab (Yervoy) in melanoma. The addition of the gp100 peptide antigen to the Ipilimumab arm provided no added clinical benefit compared to Ipilimumab alone.8 In another example, the use of a telomerase vaccine combined with established cytotoxic chemotherapy did not improve survival in untreated pancreatic cancer patients.9 The data seem clear: unmutated, normal self-antigens will not arouse the host immune system as vigorously as neo-antigens. 

However, this does not mean that vaccines containing wild-type proteins are immunologically silent. gp100 and other shared antigen vaccines, such as NY-ESO-1, have been demonstrated to induce antigen-specific
immune responses. One approach is to identify neoantigens from large numbers of patients possibly leading to the discovery of shared neoantigens among groups of cancer patients. Unfortunately, this strategy is fraught with commercial and technical problems. Preliminary observations suggest that the neoantigens recognized by T cells vary greatly from patient to patient, making creation of an off-the-shelf vaccine hard. In the long run, we believe it is premature to include solely mutated neoantigens in future cancer vaccines and in the long run, both cancer-specific shared antigens and unique neoantigens will play a role.

The impetus to make cancer vaccines is clear, but as noted above, success has been absent. What have the failed trials taught us? 

Learnings from previous failures of cancer vaccines include:

  • Forceful Delivery Method: The antigenic stimulus needs to be provided in a way that activates rather than tolerizes the host. The tumor vaccine needs to be administered to an immune system that has not returned to the basal state, that is, to a mobilized, activated immune system. If the vaccine is delivered during quiescence, the effect may be to make the stimulus even more tolerized. Dendritic cell stimulation is key to an effective stimulation of anti-tumor T cells and the presented antigens are best exposed in an immunogenic environment. Some next-generation cancer vaccines deliver antigens using new activating vectors, including Listeria monocytogenes, ensuring that the innate arm will be an operative participant.10,11

  • Use Adjuvants: Vaccines alone are inadequate: activation of innate arm of the immune system is needed in order to achieve sufficient T cell stimulation. One way to achieve this is through the use of adjuvants. Adjuvants with preclinical support in cancer vaccines include conventional agents such as alum, formulation in liposomes, and TLR agonists.12 More recent discoveries, such as STING agonists, demonstrate the ability to promote INFg signaling and a Th1-type immune response.13

  • Utilize Patient Selection: Vaccine antigens will not work in all patients and patient selection strategies will enhance the likelihood of benefit. At one end of this extreme is the elegant work from Rosenberg and colleagues at the National Cancer Institute, where the melanoma antigens that effectively stimulate the patient's T cells are identified by in vitro screening.14 This method is challenging commercially and may not be practicable in the short term. However, less customized patient selection strategies are available. For example, confirmation that the patient's tumor expresses the targeted antigen(s) is advisable. This approach was taken for the Muc1 antigen in a lung tumor vaccine trial where only tumors showing 50% or more Muc1 positive cells was an inclusion criterion, a decision which may have been crucial to its significant survival results.18 Other stratification systems can be used, including selection of specific HLA subtypes and determination of checkpoint inhibitor levels.15

  • Work with a Healthy Immune System:  It is important to study patients whose immune system is vigorous and not debilitated. Many cancer vaccine trials have tested the response of patients who have failed multiple previous treatments and these treatments, including cytotoxic therapy and radiation, compromise the patient's immune response. In general, cancer vaccines have come closest to being effective in untreated patients.

  • Appropriate Dosing: The tumor has already been exposed to most, if not all, tumor antigens. For this and other reasons, vaccination doses need to be large enough to reach levels where the afferent arm of the immune system takes notice. With the complications of running cancer vaccine trials in which patients drop out, full doses are sometimes not completed, with subsequent dilution of potential efficacy.16

Despite the continued disappointments, recent trials, implementing some of the ideas above, provide encouragement. Transgene has been working on a modified vaccinia virus vaccine which encodes both a classic self-tumor antigen, Muc1, and also provides cytokine support in the form of IL-2. Muc 1 is a cell surface glycoprotein over-expressed on multiple epithelial tumors. This vaccine or placebo was given to ~220 naïve lung cancer patients in combination with cytotoxic chemotherapy but only if 50% of the tumor cells expressed Muc1. With the intent to treat population, a statistically significant but modest increase in progression-free survival (5.9 vs. 5.1 months; p=0.019) and an increase in overall survival that was borderline significant were observed (12.7 vs. 10.6 months; p=0.55).17 When specific subsets were evaluated, two sub-groups revealed positive effects: non-squamous patients and patients with reduced levels of activated lymphocytes. Patients with both of these features achieved notably better survival (15.1 vs. 10.3 months, p=0.0072).
 

Interestingly, although the data review committee indicated the trial should continue, Transgene has discontinued this study in favor of combining its vaccine with PD-1 blockade, perhaps believing that the future of cytotoxic chemotherapy in lung cancer is cloudy.

One of the most intriguing late-stage trials is testing a vaccinia virus-enhanced prostate-specific antigen (PSA) vaccine (PROSTVAC) combined with GM-CSF. The enhancement is composed of three genes known to control the immune response (CD80, LFA3, and ICAM-1) and hence the virus is called TRICOM. Work exploring the use of vaccinia virus-based antigen presentation in prostate cancer began almost two decades ago; it has been a long road indeed! An important step forward was the realization that the humoral immune response to the virus can reduce activity, leading to the use of a fowlpox virus for boost treatments. The randomized, placebo-controlled Phase III trial of ~1300 patients (PROSPECT) is fully accrued and is using overall survival as its primary endpoint. Men must have castrate-resistant prostate cancer but must not have received chemotherapy, increasing the chance that their immune system is not weakened. The treatment grew out of a collaboration between Bavarian Nordic and the National Cancer Institute, and in 2015 BMS licensed the vaccine for a relatively modest sum of $80M.

In January this year, adjusted survival data from the randomized Phase II trial (n= ~120) were released based on a revised analysis of patient outcomes. Notably, the revised figures were even better than the previously published results, with the experimental arm achieving almost 10 months better overall survival (p=0.019).18 This exceptionally robust effect certainly provides grounds for hope, and in addition two interim analyses in 2016 confirmed that PROSPECT should continue. Bavarian Nordic indicates that the final survival data should be available in 2017.19 While it would be enigmatic for a 10-month survival benefit to vanish, it would not be the first time a highly promising Phase II study was not supported in a
registrational trial.

Clearly, cancer vaccines by themselves are unlikely to have sufficient potency to induce substantial and long-lasting tumor regressions. However, with the exception of the Ipilimumab trial mentioned above, most trials so far have not combined cancer vaccines with drugs which unambiguously stimulate anergized T cells in humans. Even the most powerful cancer vaccine, one which leads to vigorous and long-lasting T cell stimulation, will encounter both secreted and cell surface barriers in the immunosuppressive environment that tumors create. Given the compelling results in humans targeting checkpoint inhibitors, it is sensible to combine these agents with cancer vaccines. There are approximately 10 trials in progress combining pembrolizumab with a vaccine and 13 trials with nivolumab and a vaccine.20 These trials are in early stages, generally Phase I or Phase I/II, but if the early signal from adding a vaccine is evident, we can expect registrational trials to follow. 

But will the signal be strong? A look at the history of predictions for cancer vaccines suggests caution is warranted. In 1974, an editor at Science  with the initials “J.L.M.” wrote a short, prophetic commentary entitled “Cancer vaccine prospects: not soon” which concluded “Researchers are hopeful that they can develop a vaccine against human cancer, but these problems, plus the need for thorough testing for safety and effectiveness in animals before human studies can be initiated, all militate against an early solution”.21 We envision cancer vaccines making an important contribution both as better vaccines are created and as they are combined with the plethora of new agents revolutionizing cancer treatment, the multiple co-inhibitory and co-stimulatory biologic drugs in development. In addition, as we gain greater insight into both the patient's individual tumor antigens and the immunophenotype via sequencing, both vaccine design and clinical trial strategy will improve. We predict it will not take another 40 years before cancer vaccines become a crucial part of the oncologist's armamentarium but precisely when is challenging to forecast. One observation seems inescapable: further research will provide an essential foundation for the ultimate victory of this desirable but elusive way to treat cancer.

Sources:

  1. Freedman A, Neelapu SS, Nichols C, et al., Placebo-controlled phase III trial of patient-specific immunotherapy with mitumprotimut-T and granulocyte-macrophage colony-stimulating factor after rituximab in patients with follicular lymphoma. J Clin Oncol 2009; 27(18): 3036–43.

  2. Levy R, Robertson M, Ganjoo K, et al. Results of a Phase 3 trial evaluating safety and efficacy of specific immunotherapy, recombinant idiotype (Id) conjugated to KLH (Id-KLH) with GM-CSF, compared to non-specific immunotherapy, KLH with GM-CSF, in patients with follicular non-Hodgkin’s lymphoma (fNHL). AACR Annual Meeting, San Diego, CA, 2008.

  3. Schuster SJ, Santos CF, Neelapu SS, et al. Vaccination with IgM but not IgG idiotype prolongs remission duration in follicular lymphoma patients. Blood 2010; 116: 429.

  4. Mitchell P, Thatcher N, Socinski MA, et al. Tecemotide in unresectable stage III non-small-cell lung cancer in the phase III START study: Updated overall survival and biomarker analyses Ann Oncol 2015; 26(6): 1134–42.

  5. Giaccone G, Bazhenova LA, Nemunaitis J, et al. A phase III study of belagenpumatucel-L, an allogeneic tumour cell vaccine, as maintenance therapy for non-small cell lung cancer Eur J Cancer 2015; 51(16): 2321–9.

  6. De Marinis F, Vergnenegre A, Passaro A, et al. Erlotinib-associated rash in patients with EGFR mutation-positive non-small-cell lung cancer treated in the EURTAC trial. Future Oncol 2015; 11(3): 421–9.

  7. Jochems C, Tucker JA, Tsang KY, et al. A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: Immune correlates. Cancer Immunol Immunother 2014; 63(4): 407–18.

  8. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med 2010; 363(8): 711–23.

  9.  Middleton G, Silcocks P, Cox T, et al. Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): An open-label, randomised, phase 3 trial. Lancet Oncol 2014, 15(8): 829–40.

  10. 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): 1325–33.

  11. Haas N, Stein M, Tutrone R, et al. Phase 1/2 study of ADXS31-142 and pembrolizumab in metastatic castration-resistant prostate cancer (mCRPC): The KEYNOTE-046 trial. J Immunother Cancer 2015; 3(2): P153.

  12. Morse MA, Chapman R, Powderly J, et al. Phase I study utilizing a novel antigen-presenting cell-targeted vaccine with toll-like receptor stimulation to induce immunity to self-antigens in cancer patients. Clin Can Res 2011; 17(14): 4844–53.

  13. Fu J, Kanne DB, Leong M, et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci Transl Med 2015; 7(283): 283ra52.

  14. Passetto A, Gros A, Robbins PF, et al. Tumor- and neoantigen-reactive T-cell receptors can be identified based on their frequency in fresh tumor. Cancer Immunol Res 2016; 4(9); 734–43.

  15.  Shindo Y, Hazama S, Suzuki N, et al. Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer J Exp Clin Cancer Res 2017; 36(1): 36.

  16. Rodriguez P, Popa X, Martinez O, et al. A phase III clinical trial of the epidermal growth factor vaccine CIMAvax-EGF as switch maintenance therapy in advanced non-small cell lung cancer patients. Clin Can Res 2016; 22(15): 3782–90.

  17. Quiox 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): 212–23.

  18. Kantoff P, 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), 124–5.

  19. PROSTVAC phase 3 clinical study, http://www.bavarian-nordic.com/pipeline/prostvac/prospect-phase-3-clinical-study.aspx.

  20. clinicaltrials.gov – Search using pembrolizumab or nivolumab as “intervention” and “vaccine” as search term. March 2017.

  21. JL, M. Cancer vaccine prospects: Not soon. Science 1974; 183(4129): 1067.

 

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