In the current issue of ONCOLOGY,Drs. Emens and Jaffee haveprovided an excellent overview ofthe basic mechanisms involved in thetumor-specific immune response, aswell as a comprehensive update ofresearch on immune-based therapiesfor breast cancer.
In the current issue of ONCOLOGY,Drs. Emens and Jaffee haveprovided an excellent overview ofthe basic mechanisms involved in thetumor-specific immune response, aswell as a comprehensive update ofresearch on immune-based therapiesfor breast cancer.Over the past decade, several advancesin basic immunology have resultedin a renewed interest in thedevelopment of cancer vaccines. First,as reviewed by Emens and Jaffee, wehave a better understanding of howimmunogenic proteins are recognizedby the immune system, specificallyby T cells. Second, it is now understoodthat a potentially therapeuticantitumor immune response must involvea variety of immune effectors,including both cytotoxic and T-helpercells. Furthermore, the importanceof antibody immunity has been underscoredby the clinical success withmonoclonal antibodies such as trastuzumab(Herceptin). Finally, the developmentof powerful moleculartools has allowed the identification ofmultiple tumor antigens. Clearly humantumors are immunogenic.As this article emphasizes, the taskbefore us now is to harness, augment,and manipulate the tumor-specificimmune response for the benefit ofcancer patients. Recently we have begunto see significant progress in theclinical application of cancer vaccines.Koutsky and colleagues have elegantlydemonstrated that immunization ofyoung women with a vaccine targetinghuman papillomavirus (HPV)-16protects not only against the developmentof HPV infection, but most likelyagainst the development of cervicalintraepithelial neoplasia.Similarly, a large study from theSouthwest Oncology Group demonstratedthat patients with melanoma,whose disease has been completely resectedand who have specific humanleukocyte antigen (HLA)-immune phenotypes,can be immunized with a celllysate-based vaccine resulting in a significantsurvival benefit. Thus, cancervaccines may have benefit not onlyin protecting from disease developmentin high-risk individuals but also in protectingagainst cancer relapse in theadjuvant setting.Breast Cancer Is Immunogenic
Breast cancer has not classicallybeen considered an immunogenic tumor.Spontaneous regressions, however,have been reported in breastcancer patients, and several investigatorshave demonstrated that breast tumors have lymphocytic infiltratesthat may correlate with positive clinicalresponses. These are the typesof clinical observations that have beenused to identify melanoma andrenal cell carcinoma as cancers thatmay be amenable to immune-basedtherapies.The lack of investigation of theimmunologic characteristics of breastcancer (until recently) most likely layin the difficulty of documenting tumorantigen-specific immune responsesin patients. For many years,a hallmark of defining a tumor asimmunogenic has been the ability togenerate cytotoxic T lymphocytesspecific for autologous tumor anddemonstrate cytotoxic T-cell activityin vitro. Propagating primary autologousbreast cancer tumors in vitro istechnically difficult. Furthermore,many primary breast tumors are smalland pathologists often require the entirespecimen for diagnosis and staging,leaving little material availablefor research purposes.Despite the difficulties in developingexperimental systems, over thepast decade, both genomic and proteomictechniques have resulted in theidentification of dozens of immunogenicproteins that are expressed inbreast cancer. Emens and Jaffee'sTable 1 lists a few of the most commonlystudied breast cancer antigens.Role of Vaccines in theTreatment of Breast Cancer
As the authors note, vaccines targetingbreast cancer antigens are beingstudied in minimal residual diseasestates. By evaluating active immunizationin patients with functioningimmune systems and without the multipleimmunosuppressive effects ofbulky disease, breast cancer vaccinesare showing significant immunologicactivity. Several of the studies outlinedin the article demonstrate thatthe majority of patients can be immunizedagainst breast cancer antigensand generate measurable tumorspecificimmunity.A comparison of cancer vaccinesand infectious disease vaccines underscoresthe need for vaccinating in minimal disease states. The levels of T-cell immunity to a foreign infectiousantigen generated after activeimmunization is significantly less thanthe level of T-cell immunity neededto combat an active infection. Vaccinationis meant to boost immunity toa plateau level, at which point T cellscan rapidly expand to therapeutic levelsafter exposure to the pathogen.Increasingly, cancer vaccine studiesare being designed in a similar fashionto those of infectious vaccines.The first phase of study is to determinethe immunogenicity of thevaccine approach, and the nextphase is to determine whether a specificimmune response can protectagainst disease. Clearly, breast cancervaccines have demonstrated preliminarysuccess in the first phase oftesting.Evolution ofCombination Therapies
If breast cancer vaccines are to succeedin preventing relapse-a majorclinical problem at many stages ofbreast cancer-then the clinical applicationof vaccines must be wellintegrated into adjuvant treatment.Emens and Jaffee describe the challengesin such integration.It has long been assumed that chemotherapyfunctions as a direct immunosuppressant.Recent data,however, suggest that vaccinating patientsduring recovery from inducedlymphopenia may actually augmentimmune responses. Therefore,there may be a strong rationale fordeveloping vaccine programs intimatelyintegrated with the use ofchemotherapy, as described by theauthors. Furthermore, combinationimmunotherapy may augment levelsof immunity achieved after vaccination.Published data have demonstratedthat cytotoxic T cells specific forHER2 have augmented lytic activitywhen breast tumor target cells havebeen preincubated with trastuzumab. These early preclinicaldata suggest that combination therapiesmay enhance tumor-specific immunityrather than interfere withvaccination.Conclusions
In summary, there has been substantialprogress in the developmentof immune-based therapies for breastcancer. It is now well established thatbreast cancer is an immunogenic tumor.Furthermore, dozens of breastcancer antigens have been identified.As outlined by Emens and Jaffee, severalvaccine strategies targeting breastcancer have resulted in the generationof tumor-specific immune responsesin patients with the disease.Clinicians are evaluating the applicationof breast cancer vaccines in thesetting of minimal residual diseaserather than in patients with advancedstagerefractory tumors. Improvedclinical application has lead to successfultrials of the evaluation of immunogenicity.Finally, the integrationof breast cancer vaccines in the adjuvantsetting may result in improvedimmunogenicity. The field is poisedto focus on the next phase of breastcancer vaccine testing-determiningclinical efficacy.
The author(s) have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
Koutsky LA, Ault KA, Wheeler CM, etal: A controlled trial of a human papillomavirustype 16 vaccine. N Engl J Med 347:1645-1651, 2002.
Sosman JA, Unger JM, Liu PY, et al:Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanomawith an allogeneic tumor vaccine: Impact ofHLA class I antigen expression on outcome. JClin Oncol 20:2067-2075, 2002.
Challis GB, Stam HJ: The spontaneousregression of cancer. A review of cases from1900 to 1987. Acta Oncol 29:545-550, 1990.
Demaria S, Volm MD, Shapiro RL, et al:Development of tumor-infiltrating lymphocytesin breast cancer after neoadjuvantpaclitaxel chemotherapy. Clin Cancer Res7:3025-3030, 2001.
Hu HM, Poehlein CH, Urba WJ, et al:Development of antitumor immune responsesin reconstituted lymphopenic hosts. CancerRes 62:3914-3919, 2002.
zum Buschenfelde CM, Hermann C,Schmidt B, et al: Antihuman epidermal growthfactor receptor 2 (HER2) monoclonal antibodytrastuzumab enhances cytolytic activityof class I-restricted HER2-specific T lymphocytesagainst HER2-overexpressing tumorcells. Cancer Res 62:2244-2247, 2002.