Cellular Adaptive Immune System Plays a Crucial Role in Trastuzumab Clinical Efficacy

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VOLUME

28



NUMBER

21



JULY

20

2010

JOURNAL OF CLINICAL ONCOLOGY

Cellular Adaptive Immune System Plays a Crucial Role in Trastuzumab Clinical Efficacy TO THE EDITOR: We read with great interest the review by Spector and Blackwell,1 in which the authors highlight the most important mechanisms by which trastuzumab carries out its intracellular and extracellular effects against human epidermal growth factor receptor 2 (HER2) –positive breast cancer cells. The authors identified four direct trastuzumab-mediated cytotoxic effects and an indirect cytotoxic mechanism. The direct mechanisms consist in the blockage of different intracellular transduction signal cascades caused by the interaction between the HER2 and the monoclonal antibody, whereas the indirect mechanism consists in the activation of the host’s innate immune system. There is abundant evidence that demonstrates that trastuzumab, through its immunoglobulin G1 humanized Fc portion,2 is able to act as an autologous antibody3 and activate antibody-dependent cellmediated cytotoxicity by natural killer cells.4-8 We agree that antibody-dependent cell-mediated cytotoxicity is an intuitive and important immunological mechanism of trastuzumab; however, current findings have clearly demonstrated a pivotal role of the adaptive immune system in cancer control. In fact, frequently, patients with breast cancer exhibit an HER2 CD8⫹ T cell immunity. In vivo studies on murine models affected by chemically induced sarcomas demonstrated that the adaptive immune system plays a pivotal role in the tumor-host relationship and is able to maintain neoplasm in a dormancy state.9 In these models, the innate immune system played a minor role. The finding that the adaptive immune system has a key role in preventing tumor progression is in line with clinical findings carried out in several tumors,10-12 including breast cancer,13 where there is a significant correlation between tumorinfiltrating lymphocytes and prognosis. Neoplastic samples obtained from women previously treated with trastuzumab show a significant increase in CD8⫹ and CD4⫹ cells, demonstrating that this antibody can activate different mechanisms able to recruit lymphocytes in the tumor site.7 The cascade by which this antibody elicits a specific adaptive immune response begins with trastuzumab-induced HER2 downmodulation and consequent internalization. HER2/neu protein is then processed and HER2/neu-derived peptides are presented to matched specific lymphocytes on major histocompatibility complex (MHC) class I molecules.14 It has been shown that this phenomenon is dose and time dependent and takes place after saturation of all HER2/neu cellular receptors by trastuzumab.15 Trastuzumab-pretreated cancer cells show a significantly enhanced cell lysis when incubated with HER2/neu-derived peptides E75 and GP2–specific CD8⫹ T lymphocytes, thus confirming the increased epitope presentation of HER2/neu peptides on MHC class I.15 In a recent clinical trial on tumor vaccination, it was observed that women who had completed therapy with trastuzumab had a significant superior E75-specific CD8⫹ T cell response to the first Journal of Clinical Oncology, Vol 28, No 21 (July 20), 2010: pp e369-e370

C O R R E S P O N D E N C E

vaccination with E75 peptide.16 This demonstrates that the immunological effect of trastuzumab persists even after the antibody has been cleared and most importantly, that trastuzumab is able to induce a long lasting immunological effect, thereby indicating the generation of a memory immune response. Trastuzumab is also able to reduce circulating regulatory T cells (Tregs)17 and alter the balance between Tregs and TH17.18 Trastuzumab has changed the natural history of HER2/neupositive breast cancer19-24 and represents the most important proof of concept justifying the introduction in the clinical practice of target therapies. Due to the complexity of the different immunological effects, which are triggered and the different mechanisms involved, this antibody has rarely been referred to a proof of concept for immunotherapy. Burstein and Winer,25 in their knowledgeable Editorial, highlighted two future avenues that require investigation by scientists worldwide. First, they pointed out the importance of identifying tumor markers beside HER2 overexpression that can most clearly predict benefit from trastuzumab. Possibly, in addition to tumor markers, research lines should include a patient’s characteristics, such as the specific immune status before or precociously after the initiation of trastuzumab. Preliminary evidence has suggested that baseline immunologic status can predict long-lasting immune effects.26 Second, they highlighted the importance of identifying in which settings the benefits of trastuzumab can be optimized. Emerging data are showing synergic in vitro effect between trastuzumab and other target drugs27,28 that stabilize HER2.29-30 If we consider the role played by the systemic adaptive immune system in trastuzumab efficacy, the combination of these drugs could actually have an antagonizing role in vivo. Ongoing clinical trials (ClinicalTrials.gov Identifiers NCT00490139, NCT00470704, NCT00968968) will clarify the biologic relationship between trastuzumab and intracellular HER2 inhibitors. Several recently reported or ongoing trials are verifying the different clinical settings in which trastuzumab should be adopted.21,31-38 A further milestone, regarding treatment duration, will be set when the mature results of the Herceptin Adjuvant (HERA) trial (ClinicalTrials.gov Identifier NCT00045032) are available. An attractive avenue that is currently being pursued in association or after trastuzumab is HER2 peptide vaccination (Clinical Trials.gov Identifiers NCT00791037, NCT00343109, NCT00524277). Anticancer peptides are inexpensive, easily administered, and increasing evidence is showing that cellular immunity remains prolonged and efficient with infrequent boost administrations.39 Hopefully, a better understanding of the short- and long-term effects of monoclonal antibodies and possible synergies with other therapeutic strategies will allow women’s immune systems to survey and control tumor progression and protect them from disease recurrence.

Filippo Bellati, Chiara Napoletano, and Ilary Ruscito “La Sapienza” University of Rome, Italy

Marco Liberati “G. D’Annunzio” University of Chieti, Italy © 2010 by American Society of Clinical Oncology

Information downloaded from jco.ascopubs.org and provided by at SWETS SUBSCRIPTION SERVICE on April 26, 2011 Copyright © 2010 Americanfrom Society of Clinical Oncology. All rights reserved. 193.175.73.206

e369

Correspondence

Pierluigi Benedetti Panici and Marianna Nuti “La Sapienza” University of Rome, Italy

ACKNOWLEDGMENT

Supported by the Associazione Italiana Ricerca contra il Cancro (AIRC) and Ministero dell’Istruzione, dell’Università e della Ricerca (MIUR). AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest. REFERENCES 1. Spector NL, Blackwell KL: Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol 27:5838-5847, 2009 2. Lazar GA, Dang W, Karki S, et al: Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci U S A 103:4005-4010, 2006 3. Kute TE, Savage L, Stehle JR Jr, et al: Breast tumor cells isolated from in vitro resistance to trastuzumab remain sensitive to trastuzumab anti-tumor effects in vivo and to ADCC killing. Cancer Immunol Immunother 58:1887-1896, 2009 4. Cooley S, Burns LJ, Repka T, et al: Natural killer cell cytotoxicity of breast cancer targets is enhanced by two distinct mechanisms of antibodydependent cellular cytotoxicity against LFA-3 and HER2/neu. Exp Hematol 27:1533-1541, 1999 5. Mimura M, Kono K, Hanawa M, et al: Trastuzumab-mediated antibodydependent cellular cytotoxicity against esophageal squamous cell carcinoma. Clin Cancer Res 11:4898-4904, 2005 6. Repka T, Chiorean EG, Gay J, et al: Trastuzumab and interleukin-2 in HER2positive metastatic breast cancer: A pilot study. Clin Cancer Res 9:2440-2446, 2003 7. Arnould L, Gelly M, Penault-Llorca F, et al: Trastuzumab-based treatment of HER2-positive breast cancer: An antibody-dependent cellular cytotoxicity mechanism? Br J Cancer 94:259-267, 2006 8. Gennari R, Menard S, Fagnoni F, et al: Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res 10:5650-5655, 2004 9. Koebel CM, Vermi W, Swann JB, et al: Adaptive immunity maintains occult cancer in an equilibrium state. Nature 450:903-907, 2007 10. Zhang L, Conejo-Garcia JR, Katsaros D, et al: Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med 348:203-213, 2003 11. Galon J, Costes A, Sanchez-Cabo F, et al: Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 313:1960-1964, 2006 12. Eerola AK, Soini Y, Pa¨a¨kko¨ P: A high number of tumor-infiltrating lymphocytes are associated with a small tumor size, low tumor stage, and a favorable prognosis in operated small cell lung carcinoma. Clin Cancer Res 6:1875-1881, 2000 13. Aaltomaa S, Lipponen P, Eskelinen M, et al: Lymphocyte infiltrates as a prognostic variable in female breast cancer. Eur J Cancer 28A:859-864, 1992 14. zum Bu¨schenfelde CM, Hermann C, Schmidt B, et al: Antihuman epidermal growth factor receptor 2 (HER2) monoclonal antibody trastuzumab enhances cytolytic activity of class I-restricted HER2-specific T lymphocytes against HER2overexpressing tumor cells. Cancer Res 62:2244-2247, 2002 15. Mittendorf EA, Storrer CE, Shriver CD, et al: Investigating the combination of trastuzumab and HER2/neu peptide vaccines for the treatment of breast cancer. Ann Surg Oncol 13:1085-1098, 2006 16. Benavides LC, Gates JD, Carmichael MG, et al: The impact of HER2/neu expression level on response to the E75 vaccine: From U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res 15:2895-2904, 2009 17. Perez SA, Karamouzis MV, Skarlos DV, et al: CD4⫹CD25⫹ regulatory T-cell frequency in HER-2/neu (HER)-positive and HER-negative advanced-stage breast cancer patients. Clin Cancer Res 13:2714-2721, 2007 18. Horlock C, Stott B, Dyson PJ, et al: The effects of trastuzumab on the CD4⫹CD25⫹FoxP3⫹ and CD4⫹IL17A⫹ T-cell axis in patients with breast cancer. Br J Cancer 100:1061-1067, 2009 19. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 20. Tripathy D, Slamon DJ, Cobleigh M, et al: Safety of treatment of metastatic breast cancer with trastuzumab beyond disease progression. J Clin Oncol 22:1063-1070, 2004

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DOI: 10.1200/JCO.2010.28.6922; published online ahead of print at www.jco.org on May 17, 2010

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© 2010 by American Society of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY

Information downloaded from jco.ascopubs.org and provided by at SWETS SUBSCRIPTION SERVICE on April 26, 2011 Copyright © 2010 Americanfrom Society of Clinical Oncology. All rights reserved. 193.175.73.206

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