Cancer Vaccines: Moving Toward Prevention?

Cancer Prevention Perspective Research Perspective on Berta et al., p. 994

Cancer Vaccines: Moving toward Prevention?

Larry W. Kwak1,2

Abstract After several decades of research, recent successful phase III controlled clinical trials have renewed enthusiasm for vaccine treatment of cancer. This perspective on the report by Berta and colleagues in this issue of the journal (beginning on page 994) discusses the potential prevention of oral cancer through vaccine strategies and, in the broader context, ideal characteristics of tumor antigens as candidates for vaccines for both treating and preventing cancer, potential primary and secondary prevention settings for vaccines, desirable types of immune effectors induced by vaccines, and safety. Cancer Prev Res; 4(7); 954–6. Ó2011 AACR.

Often the development of a new class of cancer therapeutic polyclonal, that is, elicited against multiple determinant agents is characterized by a wave of initial (naive) enthu- influences on the targeted antigen, thereby rendering the siasm, followed by rejection associated with early failures, possibility of escape by alteration of a single determinant and ultimately real progress and renewed optimism as (e.g., mutation) much less likely. obstacles are more fully understood and overcome. This Application of this simplistic concept soon gave way, roller coaster of successes and failures was experienced by however, to the reality of the complexity of suitable candi- monoclonal antibody therapeutics prior to their incorpora- date cancer antigens, suboptimal vaccine delivery plat- tion into standard of care (1) and now, a decade later, by forms, and the lack of available practical immune cancer vaccines. adjuvants for use in humans. Not the least obstacle was The cancer vaccine hypothesis was first proposed in clinical application—cancer vaccines were administered in response to the success of childhood vaccines against a therapeutic setting against advanced cancer burdens, infectious pathogens. Briefly, the idea is that like childhood distinguishing them from childhood vaccines, which are vaccines (which contain parts of the bacteria or virus), there administered in a prevention setting absent established are proteins (antigens) that are either specifically expressed disease. Not surprisingly in view of these substantial obsta- or overexpressed by tumor cells compared with normal cles, most early therapeutic cancer vaccines met with failure cellular counterparts, and that these antigens can be iden- in large phase III controlled clinical trials. An in-depth tified, isolated, and packaged into appropriate delivery analysis of how these obstacles have been overcome in systems. If successful, the injected cancer vaccine activates recent years is beyond the scope of this perspective. How- the host immune system. Unlike most anti-cancer thera- ever, one clear advance by the field has been to replace peutics, vaccines work indirectly by activating adaptive crude tumor-cell extracts with well-defined, highly purified immunity (antibodies and T-cells), because they have no cancer vaccine products. Tumor antigen candidates for direct anti-cancer effect. Major theoretical advantages of current state-of- the-art cancer vaccine development have this type of active immunotherapy, compared with passive the following characteristics: (i) Specific expression or immunotherapy with monoclonal antibodies, include that overexpression by tumor cells compared with normal cells, the immune response will be entirely host-derived, that is, (ii) demonstrated immunogenicity (i.e., recognizable by containing no mouse or other xenogeneic component. For the immune system) and oncogenicity (i.e., expression this reason, the immune responses may be sustained and required for tumor cell survival), and (iii) cell-surface not require frequent administrations, such as is required for expression, either as an intact protein (required for the chemotherapy or passive immunotherapy, aside from occa- target of an antibody response) or as a peptide in the groove sional boosters. Finally, the immune response will be of a human leukocyte antigen (HLA) molecule (target of a T-cell response). Such technical and conceptual advances have catalyzed an upward trajectory of renewed enthusiasm Author's Affiliations: 1Department of Lymphoma and Myeloma and for cancer vaccines and placed them directly back onto a 2 Center for Cancer Immunology Research, The University of Texas MD path of accelerated development, underscored by recent Anderson Cancer Center, Houston, Texas reports of at least 3 positive phase III controlled clinical Corresponding Author: Larry W. Kwak, Department of Lymphoma and Myeloma, University of Texas MD Anderson Cancer Center, 1515 Hol- trials of cancer vaccines in diverse tumor types, including combe Boulevard, Unit 429, Houston, TX 77030. Phone: 713-745-4252; melanoma, lymphoma, and prostate cancer, for which the Fax: 713-563-4625; E-mail: [email protected] first-in-class regulatory approval of a cancer vaccine was doi: 10.1158/1940-6207.CAPR-11-0236 granted by the U.S. Food and Drug Administration in Ó2011 American Association for Cancer Research. May 2010 (Provenge; refs. 2–4). There is optimism that

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these 3 recent successes herald the development of other are felt to be even more relevant as effector cells recognizing such therapeutic vaccines for cancer. and lysing human tumor cells (8, 9), is unanswered One question is whether "cancer" vaccines can ever be because of technical constraints of the model. applied in the setting of primary cancer prevention (pre- A recently reported clinical trial of a lymphoma vaccine vention of tumor development)? One can certainly point to also provides potentially relevant information, as it is an commercially available vaccines against human papilloma- example of secondary cancer prevention (or the prevention virus and hepatitis B as examples of vaccines which prevent of recurrence). Previous preclinical studies in animal mod- cervical and liver cancer, respectively, but strictly speaking, els showed optimal antitumor effects of the identical vac- both are vaccines against viruses (albeit cancer-related) cine in the setting of minimal residual disease rather than rather than against neoplastic cells. However, several stu- against advanced tumor burdens (10), and a phase II study dies in animal models now suggest that targeting antigens validated this strategy in patients (11); based on these data, a directly expressed by tumors with vaccines can prevent randomized double-blind, controlled multicenter phase III cancer development. For example, Jaini and colleagues clinical trial was conducted to formally determine the (5) targeted the breast-cancer antigen alpha-lactalbumin clinical efficacy of this vaccine, which consisted of the with a vaccine containing the recombinant protein mixed unique B-cell–receptor protein isolated from the surface with complete Freund’s adjuvant, which provided signifi- of each patient’s tumor, coupled to a carrier protein, and cant protection against development of autochthonous mixed with an adjuvant. The investigators selected follicular tumors in transgenic mouse models of breast cancer. lymphoma as the target disease, taking advantage of the Because this antigen is a breast-specific differentiation frequent remissions followed by inevitable relapse after protein conditionally expressed only during lactation standard chemotherapy in this low-grade lymphoma. (and on human breast carcinoma cells), there was no Therefore, patients with previously untreated follicular lym- collateral inflammation of normal, nonlactating breast phoma were treated with uniform chemotherapy, and tissue. Therefore, it was proposed for development as safe patients with a complete remission (CR) were then rando- prophylaxis against breast cancer development in post- mized to receive either active or a control vaccine (consisting child-bearing women. Beatty and colleagues (6) targeted of carrier protein and adjuvant). The primary endpoint was a true tumor antigen, human mucin 1 (MUC1), an epithe- disease-free survival. Of 234 enrolled patients, 177 had a CR lial mucin aberrantly expressed during chronic inflamma- and were subsequently randomized to receive either active tion and colorectal carcinogenesis, with a long peptide or control vaccine. Of these 177 patients, 117 maintained vaccine corresponding to the extracellular region of remission for a 6-month interval between the end of che- MUC1. This vaccine in an adjuvant (a substance which motherapy and beginning of vaccination (a rest period to provides nonspecific immune stimulation) prevented pro- allow for immune reconstitution) and thus were eligible to gression to colon cancer in a mouse model of inflammatory receive vaccine therapy. This prospective, modified intent- bowel disease that progresses to colitis-associated colon to-treat analysis included 76 patients on active vaccine and cancer. The vaccination was associated mechanistically 41 patients on control vaccine. The two arms were balanced with induction of MUC1-specific antibodies and cytotoxic for International Prognostic Index and other relevant clin- T cells, which eliminated abnormal MUC1-bearing cells in ical factors. After a median follow-up of 56.6 months (range colons with inflammatory bowel disease. 12.6–89.3 months), median time to relapse after randomi- The report by Berta and colleagues in this issue of the zation was 44.2 months (active vaccine) versus 30.6 months journal (7) takes this concept of prevention one step (control vaccine arm; P ¼ 0.045; HR ¼ 1.6; ref. 2). Two other further. Here the authors show that a DNA vaccine against phase III trials of similar lymphoma vaccines subsequently an archetypal oncoantigen, ERBB2, which is transiently reported negative results, but only the first of these 3 trials overexpressed in Syrian hamsters during chemical carcino- used an induction program associated with a high CR rate genesis, can reduce the severity of intraepithelial and inva- and then restricted vaccine treatment to CR patients. It is sive oral lesions. There are some minor quibbles with the tempting to speculate that minimal residual disease, as robustness of the results. For example, true protection was exemplified by CR, is necessary for the clinical antitumor not observed as a result of vaccination and the magnitudes effect of this lymphoma vaccine. of differences observed between immunized and control Another recent example of an effective cancer vaccine in hamsters in severity of intraepithelial and exophytic lesions the secondary prevention setting is a glioblastoma multi- seem small, although they are statistically significant. Since forme vaccine tested in a phase II trial (12). This trial gave a studies addressing the expression of ERBB2 in human vaccine consisting of an epidermal growth factor receptor intraepithelial oral lesions have yielded conflicting results, variant III (EGFRvIII) peptide to 18 patients with newly one could also question how well the model mimics the diagnosed EGFRvIII-expressing glioblastoma multiforme human condition. The finding of specific antibody who had minimal residual disease after surgical resection responses which correlated inversely with pathological of more than 95% of tumor volume. The vaccine’s 6-month score in immunized animals, however, provides proof of progression-free survival rate was 67% and median overall principle that an immune response against an oncoantigen survival was 26 months. After adjustment for age and can impede progression of carcinogenesis. Unfortunately, performance status, overall survival strongly favored the question of induction of antigen-specific T cells, which vaccinated patients compared with a control group

www.aacrjournals.org Cancer Prev Res; 4(7) July 2011 955

matched for eligibility criteria and prior temozolomide discussed earlier (2), or could be transiently expressed treatment (HR ¼ 5.3, P ¼ 0.0013). onnormaltissues(e.g.,alpha-lactalbumin,ref.5),or Taken together, these recent developments suggest the could have a pattern of expression restricted to normal time is ripe for extending cancer vaccines, arguably the tissues which are relatively expendable for survival (e.g., ultimate targeted therapy, to the prevention setting. Well- prostate-specific antigen). Finally, it will be exciting to recognized potential target diseases include indolent integrate vaccines for cancer therapy or prevention with hematologic tumors such as chronic lymphocytic leuke- emerging new agents designed to release immune sup- mia and Waldenstrom’s macroglobulinemia, which do pression, a barrier normally associated with established not require cytotoxic treatment in an early, asymptomatic tumors (13) but potentially operative in the setting of stage, and premalignant conditions such as monoclonal premalignant disease as well. gammopathy of uncertain significance and, considering the work of Berta and colleagues, high-risk oral intrae- Disclosure of Potential Conflicts of Interest pithelial neoplasia. In the interest of safety including avoiding collateral damage to normal tissues, another The author reports the following potential conflicts of interest: Paid high-priority area for investigation is suitable candidate consultant of Biovest International; paid consultant of and holds equity in tumor antigens to target with vaccines; target antigens Antigenics; holds equity in Xeme BioPharma, Inc; and receives research funding from Celgene. could be absolutely tumor-specific (expression restricted to the tumor, never by any normal tissues), such as the Received January 31, 2011; revised April 12, 2011; accepted May 12, one targeted by the customized lymphoma vaccine 2011; published online July 6, 2011.

References 1. Arteaga CL. Inhibiting tyrosine kinases: successes and limitations. esis in random-bred hamsters. Cancer Prev Res 2011;4: Cancer Biol Ther 2003;2(4 Suppl 1):s79–83. 994–1001. 2. Schuster S, Neelapu S, Gause B, Janik J, Muggia F, Gockerman J, 8. Disis ML. The ultimate in cancer chemoprevention: cancer vaccines. et al. on behalf of the BV301 Phase III Study Investigators. Vaccination Cancer Prev Res 2010;3:438–46. with patient-specific tumor-derived antigen in first remission improves 9. Neelapu SS, Lee ST, Qin H, Cha SC, Woo AF, Kwak LW. Therapeutic disease-free survival in follicular lymphoma. J Clin Oncol 2011 [Epub lymphoma vaccines: importance of T-cell immunity. Expert Rev Vac- ahead of print]. cines 2006;5:381–94. 3. Schwartzentruber DJ, Lawson D, Richards J, Conry RM, Miller D, 10. Kwak LW, Young HA, Pennington RW, Weeks SD. Vaccination with Triesman J, et al. A phase III multi-institutional randomized study of syngeneic, lymphoma-derived immunoglobulin idiotype combined immunization with gp100:29-217(210M) peptide followed by high- with granulocyte/macrophage colony-stimulating factor primes mice dose IL-2 compared with high-dose IL-2 alone inpatients with meta- for a protective T-cell response. Proc Natl Acad Sci U S A 1996;93: static melanoma. J Clin Oncol 2009;27:18s. 10972–7. 4. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, 11. Bendandi M, Gocke CD, Kobrin CB, Benko FA, Sternas LA, Penning- et al. Sipuleucel-T immunotherapy for castration-resistant prostate ton R, et al. Complete molecular remissions induced by patient- cancer. N Engl J Med 2010;363:411–22. specific vaccination plus granulocyte-monocyte colony-stimulating 5. Jaini R, Kesaraju P, Johnson JM, Altuntas CZ, Jane-Wit D, Tuohy VK. factor against lymphoma. Nat Med 1999;5:1171–7. An autoimmune-mediated strategy for prophylactic breast cancer 12. Sampson JH, Heimberger AB, Archer GE, Aldape KD, Friedman AH, vaccination. Nat Med 2010;16:799–803. Friedman HS, et al. Immunologic escape after prolonged progression- 6. Beatty PL, Narayanan S, Gariepy J, Ranganathan S, Finn OJ. free survival with epidermal growth factor receptor variantIII peptide Vaccine against MUC1 antigen expressed in inflammatory bowel vaccination in patients with newly diagnosed glioblastoma. J Clin disease and cancer lessens colonic inflammation and prevents Oncol 2010;28:4722–9. progression to colitis-associated colon cancer. Cancer Prev Res 13. Schabowsky RH, Madireddi S, Sharma R, Yolcu ES, Shirwan H. 2010;3:438–46. TargetingCD4þCD25þFoxP3þ regulatory T-cells for the augmenta- 7. Berta GN, Sprio AE, Iezzi M, Spadaro M, Cappia S, Salamone P, tion of cancer immunotherapy. Curr Opin Invest Drugs 2007;8: et al. A DNA vaccine against ERBB2 impairs chemical carcinogen- 1002–8.

956 Cancer Prev Res; 4(7) July 2011 Cancer Prevention Research

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Cancer Prev Res 2011;4:954-956.

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