Program Summary 2017 Breast Immune-Oncology Conference: Emerging Opportunities-Enhancing Awareness of Clinical Trials
Conference Purpose The goal of this conference is to examine the role of the immune system in breast cancer, along with the rationale for immunotherapy as a treatment for breast cancer, and the results from ongoing clinical trials of immunotherapies in breast cancer. Learn of current opportunities for trials actively accruing in breast immune-oncology. Attendees will learn about the about appropriate clinical trials of immunotherapies for patients with breast cancer, as well as gain insights into the use of standard therapies such as chemotherapy and radiation and where how these modalities impact both favorably and unfavorably on the tumor immune response. Needs Summary Over the last decade, advances in the understanding and therapeutic targeting of biologic and genetic mechanisms involved in the pathogenesis of breast cancer have steadily enhanced clinical outcomes. One of the more promising therapeutic advances in oncology in general, has been the emergence of immunotherapeutic strategies as an effective management approach. Over the last several years, advances have been made in understanding and exploiting the biology of normal hematopoietic and lymphoid stem cells in an attempt to effectively re-engineer and direct the immune system against cancer. Based on the success of immunotherapeutic agents in the treatment of melanoma, and more recently in lung cancer, it is expected that immunotherapeutic strategies will be proven efficacious for the treatment of patients with many other solid tumor types. Interest in evaluating immunotherapy in breast cancer has historically been limited based on the belief that breast tumors were non-immunogenic. However, breast cancer research suggests that we are on the verge of a transformation in the treatment of this disease. Recent data have shown that breast cancers, particularly HER2- positive and triple-negative tumors, are in fact immunogenic, and that the extent of the immune response correlates with prognosis. Emerging results from clinical trials evaluating immunotherapeutic agents, including vaccines and immune checkpoint agents, in breast cancer have shown promise, leading to increased enthusiasm for immunotherapy approaches. Ongoing and future studies will evaluate novel immunotherapeutic strategies to include combination therapy regimens that will define the role of immunotherapy in the management of breast cancer. These scientific advances in immune drug development and understanding the mechanisms underlying anti-tumor immune responses in breast cancer, will soon challenge the relevancy of current guidelines for clinical practice. Clinicians need to be prepared to understand these advances so that they can quickly incorporate them into clinical practice.
Conference Scope/Details One day meeting national in scope. We would recruit from local Florida region with the help of FLASCO, but we anticipate an expected high level of interest because of the specificity of the topic. Other meetings are either general immunotherapy in oncology, or very specific to melanoma and lung cancer Program Chair: Brian J Czerniecki, MD Location - Moffitt Cancer Center Stabile Research Building (SRB) This includes the Ted and Marty Couch Auditorium, the Atrium and the Catering Prep Room. Date October 7, 2017. Accreditation Rush University Medical Center Planning Committee Brian J Czerniecki MD, PhD Moffitt Cancer Center Mary (Nora ) Disis, MD University of Washington Gary Koski, PhD Kent State University Sungjune Kim, MD, PhD Moffitt Cancer Center Jose Conejo-Garcia, MD, PhD Moffitt Cancer Center Leisha Emens, MD, PhD, Johns Hopkins University Faculty: Guido Kroemer, MD, PhD University of Paris (Keynote Address) Brian Czerniecki, MD, PhD Moffitt Cancer Center Leisha Emens, MD, PhD Johns Hopkins University Beth Mittendorf, MD PhD University of Texas, MD Anderson Cancer Center Jose Conejo-Garcia, MD, PhD Moffitt Cancer Center Rita Nanda, MD University of Chicago Sylvia Formenti, MD New York University Hatem Soliman, MD Moffitt Cancer Center Heather Han, MD Moffitt Cancer Center Hung Khong, MD Moffitt Cancer Center
The planning committee and the faculty are all leaders in the field of breast oncology and active principle investigators in breast cancer immunology protocols. The program presentations are being formulated currently but cover a broad range of topics. In addition to further enhance the education of physicians and the public a Themed Research Topic in Breast Immunoncology has been proposed and being develop for the Journal of Frontiers in Immunology. This will further enhance awareness on breast immunotherapy clinical trials. Ancillary Patient/Advocate Session We will develop an ancillary conference as part of the main immunotherapy conference to be held the afternoon prior to the main clinician conference. This conference will be an immunology primer in breast oncology for patient advocates and patients. The objective will be to provide a background in breast immunology. This immunology breast primer will consist of 3-30 minute lectures in breast immunoncology for non-immunology lay persons; 1) Basics of the Immune Response; 2) The basic building blocks utilized in breast immunoncology (antibodies, cellular immune therapies; 3) Potential Immune Activity of standard therapies in breast oncology (radiation and chemotherapy). This conference will be videotaped and made available to those that cannot attend the conference. Drs. Koski, Czerniecki and Kim will prepare and deliver the lectures in a lay format. The video collection will be available on line through Moffitt Cancer Center for patients and advocates contemplating participating or supporting immune based therapy trials to view. They will also be available in our patient and family center. Intended Audience The intended audience for this annual one-day program includes: Medical oncologists, clinical investigators, immunology researchers that that are breast cancer oriented. Additional audiences benefiting from this program include nurses, pathologists, postdoctoral fellows involved in breast cancer research and its translation into clinical practice, and graduate students. Patient advocates, caregivers and patients can also benefit from the program and the special primer course for non-medical attendees.
Learning Objectives Upon completion of this activity, participants will be able to: 1. Review fundamentals of immunology to develop a baseline of scientific understanding that can be applied to clinical translation 2. Describe cancer immunotherapy principles in the context of current therapy decisions for the treatment of breast cancer 3. Discuss promising immunotherapy approaches for breast cancer, including vaccines and the role of checkpoint blockade 4. Determine how knowledge of response criteria and biomarkers in other tumor types may be used or applied to provide insight in assessing response to immunotherapy 5. Summarize data from recent and ongoing clinical trials of vaccines and immunotherapies as well as combination therapies currently being studied in breast cancer Draft Agenda Friday October 6 th Primer in Immunology for the Lay Person 400 pm-430pm The basics of the immune response (Koski) 430pm-500pm 500pm-530pm The Immune tools we have available in tumor immunotherapy (Czerniecki) What has been successful in the field of Immunotherapy (Sungjune Kim)
Saturday October 7 th Conference in Immune-Oncology of the Breast: An Emerging Field Conference Chair Welcome Objectives and Sessions 800 am-10:00 am Session I Impact of Immune Response on Breast Cancer Break o Principles of Breast Tumor Immunology (Jose Conejo-Garcia/Co-chair) o How understanding the Breast Immune Response will lead to Improved Therapeutic Opportunities (Guido Kroemer) o Utilizing the Immune Response as a Predictor of Outcomes in Breast Cancer (Brian Czerniecki) 10:30 am-12:00 pm Session II Clinical Applications of Immunotherapies in Breast Cancer o o o Checkpoint Blockade in Breast Cancer: Lessons Learned and opportunities going forward (Rita Nanda) The potential Role of Vaccines in Breast Cancer: What are the Opportunities (Beth Mittendorf) Restoring Th1 Immunity in in HER-2+ Breast Cancer (Heather Han) Lunch 1200-100 1:00 pm -3:00 pm Session III Combinations of Immune Therapies with Other Standard Therapies o Combining Chemotherapy with Immune Based Therapies (Leisha Emens) o Radiation as an Immunologic Weapon in Breast Cancer (Sylvia Formenti) o Potential of Anti-estrogen Therapies in Combination with Immunotherapy (Hung Khong) o Utilizing Oncolytic Virus in Combination with Chemotherapy (Hatem Soliman) Summary and Concluding Remarks Panel and Audience Discussion on Challenges, Types of Trials, insights, and Future in Breast Cancer Immunology and Immunotherapy.
Needs Assessment Breast cancer remains a leading cause of death in women (1). Recent evidence suggest the immune response plays a major role in breast cancer outcomes (2, 3, 4). Specifically the type I helper response appears particularly important especially in HER-2 expressing breast cancer (5). Loss of anti-oncodriver Th1 responses occurs early during breast tumorigenesis even during DCIS but is further obliterated as invasion occurs (6). We have shown restoration of this response predicts response to neoadjuvant therapy as well as predicts long disease free survival (7, 8). Interestingly high levels of systemic CD4 Th1 responses appears to account for successful outcomes in immunotherapies and can be transferred to susceptible animals for protection (9). There are now multiple clinical trials in breast cancer that utilize the immune response that are being tested alone and in combination with standard surgery, chemotherapies, hormonal therapy and radiation therapy. These therapies and trials will only rapidly accrue and advance the field of breast immunoncology if we provide sufficient education in the field of breast immunology to oncologists and healthcare providers, patient advocates as well as patients and caregivers. We will thus develop a breast immunoncology program that will provide education for these groups to enhance awareness of immunotherapy trials available in breast cancer and to enhance accrual to these trials. It is expected that the education of medical oncologists, primary care physicians, patient advocates, patients and care givers in the field of breast immunoncology will result in awareness of clinical trials available to breast cancer patients will increase referrals and participation in these trials. In addition, providing incidental expenses to patients with limited means including minority patients and underserved populations will increase participation and translate into meaningful immune based therapies for highrisk breast cancer patients. Perceptions of Immunotherapy: Clinical trial participation rates remain very low for patients with breast cancer and other clinical trials (ref). Interestingly rates of participation in our type I HER2 pulseddendritic cell vaccine (DC1) was almost 40%. In addition, patients are frequently requesting immune based trials in both early and late breast cancer suggesting breast immunoncology may be differently reviewed by patients and physicians. In fact minority patient groups often are not interested in standard therapies (9) but may view immunotherapy as alternative or complementary medicine therapies and may be more disposed to participate in such trials. Immunotherapy in Breast Cancer: The role of the immune response in breast cancer is becoming clear. Breast cancer was originally felt to be a non-immunogenic cancer however much recent attention has focused on the role immune response plays in outcomes. Increased lymphocyte infiltrates in breast cancer is associated with improved survival (2,3,4). In addition, we have demonstrated that the loss of anti-her-2 and HER-3 CD4 Th1 responses occurs during the development of invasive breast cancer (6, 10) and that complete responses to neoadjuvant therapy and prolonged disease free survival are associated with increased anti-oncodriver Th1 responses in the peripheral blood (7, 8, 10). Checkpoint inhibitor administration in triple negative breast cancer has led to meaningful regressions and improved survival in a small but significant number of patients (11, 12). Vaccines and other immune based therapies are being tested in various stages of breast cancer and thus a new area of immunotherapy for breast cancer has begun.
Education of Physicians and Patients in Immunotherapy: This explosion in immunotherapy has rapidly developed and physicians including medical oncologists, patient advocates and patients would benefit from education in understanding the immune response in breast cancer and the rationale and types of immunotherapies being tested in patients with breast cancer. Improving education for all groups will not only increase awareness but educating these groups will increase accrual on trials, increase funding for immune therapy trials and more rapidly move immune based therapies into the standard of care with surgery, radiation, chemotherapy and hormonal therapy. We will initiate a symposium that will address breast immunoncology to provide education, and increase awareness for patients. In addition, we will utilize some funds to support costs to facilitate minority participation in breast immunotherapy trials. References 1. Siegel RL, Miller KD, Jemal, A. Cancer statistics, 2016. CA: Cancer Journal for Clinicians. 2016. 66 (1):7-30. 2. Liu, S., et al., CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal- like breast cancer. Breast Cancer Res, 2012. 14(2): p. R48. 3. West, N.R., et al., Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer. Breast Cancer Res, 2011. 13(6): p. R126 4. Fridman, W.H., et al., The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer, 2012. 12(4): p. 298-306. 5. Perez, E.A., et al., Genomic analysis reveals that immune function genes are strongly linked to clinical outcome in the North Central Cancer Treatment Group n9831 Adjuvant Trastuzumab Trial. J Clin Oncol, 2015. 33(7): p. 701-8. 6. Datta J, Rosemblit C, Berk E, et al. Progressive Loss of Anti-HER2 CD4+ T- helper Type 1 Response in Breast Tumorigenesis and the Potential for Immune Restoration. OncoImmunology. 2015: 4:8, e1022301. DOI:10.1080/2162402X.2 7. Datta, J., et al., Anti-HER2 CD4(+) T-helper type 1 response is a novel immune correlate to pathologic response following neoadjuvant therapy in HER2-positive breast cancer. Breast Cancer Res, 2015. 17(1): p. 71. 8. Datta J, Fracol M, McMillan MT, Berk E, Lowenfeld L, Xu S, Goodman N, Lewis DA, Roses RE, DeMichele A, Czerniecki BJ. Depressed anti-her-2 CD4 Th1 type response is associated with recurrence in completely treated HER-2 positive breast cancer patients: Role for Immune Monitoring. JAMA Oncol 2 (2) 242-246 2016. doi:10.1001/jamaoncol.2015.5482. 9. Murthy, VH, Krumholz HM, Gross CP. Participation in cancer clinical trials, race,- sex-, and age-based disparities. Jama 2004: 291 (22) 2720-2726 doi:10.1001/jama.291.22.2720. 10. Fracol M, Datta J, Lowenfeld L, Xu S, Zhang PJ, Fisher CS, Czerniecki BJ. Loss of anti-her-3 CD4+ T- helper Type 1 immunity occurs in breast tumorigenesis and is negatively associated with outcomes. Annals of Surgical Oncology. 2017. 24 (2) 407-417 doi: 10.1245/s10434-016-5584-6.
11. Nanda R, Chow LQ, Dees EC, et al. A phase Ib study of pembrolizumab (MK- 3475) in patients with advanced triple-negative breast cancer. Paper presented at: 2014 San Antonio Breast Cancer Symposium; December 9-13, 2014; San Antonio, TX. Abstract S1-09. 12. Emens LA, Braiteh FS, Cassier P, et al. Inhibition of PD-L1 by MPDL3280A leads to clinical activity in patients with metastatic triple-negative breast cancer (TNBC). Presented at: 2015 AACR Annual Meeting; April 18-22; Philadelphia, PA. Abstract 6317.