Improving the Overall Understanding of Immunotherapy in Multiple Myeloma Webinar 3, September 17, 2015 Engineering the Immune System to Recognize Myeloma Cells Speakers Moderator: David Avigan, MD Harvard Cancer Center Boston, Massachusetts Faculty: Ivan Marques Borrello, MD Johns Hopkins Sidney Kimmel Comprehensive Cancer Center Baltimore, Maryland Edward A. Stadtmauer, MD University of Pennsylvania Abramson Cancer Center Philadelphia, Pennsylvania Engineering the Immune System to Recognize Myeloma Cells 1
The Four Pillars of Cancer Therapy Surgery Radiation therapy Chemotherapy Immunotherapy Monoclonal antibodies Vaccines Adoptive cell transfer Checkpoint inhibitors Immune System Basics Engineering the Immune System to Recognize Myeloma Cells 2
How the Immune System Works Defends you against various germs or foreign invaders that cause infection, illness, or disease Bacteria Viruses Fungi Parasites How Does the Body Fight Against Foreign Invaders? Immunity Innate (natural) Defender components are always ready to defend you Your first line of defense against invaders that get into your body Adaptive (acquired or specific) The invader awakens your immune cells to mount their defense Can have a longlasting effect against future invaders Engineering the Immune System to Recognize Myeloma Cells 3
Your Defense Team Lineup Natural killer cells Macrophages Dendritic cells T cells B cells Innate Adaptive NK, natural killer. Immunotherapy Directing the immune system to fight cancer Engineering the Immune System to Recognize Myeloma Cells 4
Why May Myeloma Cells Hide From the Immune System? They look too much like normal cells and so are not identified as foreign. Antigen presentation on myeloma cells in a way that favors tolerance Myeloma may inactivate normal T cells Myeloma may increase presence immune inhibiting cells in the tumor microenvironment Myeloma cells have increased activity of immune inhibiting pathways Cancer Immunotherapies Already Available Checkpoint Inhibitors mabs Vaccine mabs 1990s 2000s mabs are used in a variety of solid and heme tumors examples include rituximab (Rituxan), trastuzumab (Herceptin), alemtuzumab (Campath) Vaccines are being used in prostate cancer one example is sipuleucel-t (Provenge) Checkpoint inhibitors are being used in melanoma for example, ipilimumab (Yervoy) mabs, monoclonal antibodies. Engineering the Immune System to Recognize Myeloma Cells 5
Harnessing the Immune System to Fight Myeloma Types of Immunotherapy Monoclonal Antibodies Vaccines Chimeric Antigen Receptor (CAR) T Cells Antigen CDC C1q MAC Direct effects Monoclonal antibody ADCC Fc receptor Myeloma cell Lysis NK cell 1. Extract WBCs from patient 3. Infuse MM-targeted cells back to patient 2. Modify and expand cells in lab Cell death Webinar 1 Webinar 2 Webinar 3 Immune Cell Therapy Engineering the Immune System to Recognize Myeloma Cells 6
Immune Cell Therapy What is it? It is an infusion of autologous MM-directed T cells How are the T cells directed to MM cells? How does it work against myeloma? In two main ways: 1. Patient s T cells are harvested and then engineered in a lab to be able to identify specific surface markers on MM cells 2. These engineering T cells are then stimulated in a lab to make them more active and to proliferate and grow Infused, MM-directed T cells directly kill MM cells and stimulate T-cell immunity Types of Immune Cell Therapy Chimeric antigen receptor (CAR) T cells T-Cell Receptor (TCR) engineered T cells Marrow-infiltrating lymphocytes (MILs) Engineering the Immune System to Recognize Myeloma Cells 7
Engineered T Cell Therapy TCR transgene Myelomaspecific TCR eg MAGE-A3 TCR OR Peripheral blood T cells Chimeric antigen receptor (CAR) transgene Tumor-specific CAR (for example, anti-cd19) In vitro T cell expansion Adoptive T cell therapy T cells kill myeloma cells CAR T Cell Therapy in Multiple Myeloma Myeloma patients with disease progression within 1 yr of prior ASCT Second ASCT Patient outcome evaluated CTL019 infusion CART T cell therapy: CTL019 MM precursor cell surface target: CD19 Preliminary results of phase 1 study 10 patients treated 6 patients with ongoing responses 1 patient (so far) attained minimal residual disease (MRD)-negative scr for > 1 year Garfall AL et al. N Engl J Med. 2015;373:1040. scr, stringent complete response Engineering the Immune System to Recognize Myeloma Cells 8
Additional Studies of CAR T Cell Therapy in Multiple Myeloma Study CAR T Cell Therapy MM Surface Target Patient Population Results Institution 1 CAR. Kappa light chains Relapsed Infusion safe Modest antimyeloma activity (3 patients with stable disease) Baylor College of Medicine 2 CART-138 CD138 Refractory Safe, feasible, tolerable 4 of 5 patients with stable disease China 1. Ramos CA et al. Presented at the American Society of Blood and Marrow Transplantation meeting. February 2014. Grapevine, Texas. Abstract 6. 2. Guo B et al. J Cell Immunother. 2015; in press. Marrow-Infiltrating Lymphocytes (MILs) Features of MILs 1. Extract MILs from patient MILs Stimulated MILs 2. Stimulate and expand MILs in lab Broad antigenic specificity Ability to traffic to the BM Persistence over time 3. Infuse stimulated MILs back to patient Engineering the Immune System to Recognize Myeloma Cells 9
Marrow-Infiltrating Lymphocytes (MILs) Newly diagnosed or relapsed myeloma patients MILs collection, expansion, and activation Initial therapy Autologous stem cell transplant Myeloma-specific activity measures Activated MILs reinfusion Phase 1 study to examine feasibility, safety, and efficacy Results showed A strong correlation between clinical outcome and tumorspecific activity Achieving at least a 90% reduction in disease burden increased progressionfree survival Noonan KA et al. Sci Transl Med. 2015;7:288ra78. Questions & Answers Engineering the Immune System to Recognize Myeloma Cells 10
Question Are there any complications to the patient with these engineered T cell therapies? Question Are the engineered cells able to be self sustaining? Or do you have to use ongoing infusions to maintain the effect? Engineering the Immune System to Recognize Myeloma Cells 11
Question What is the appropriate setting for these therapies? Question How does a patient s age impact these therapies? Engineering the Immune System to Recognize Myeloma Cells 12
Question Are these therapies affordable and accessible to patients? We wish to thank the faculty for their contributions and Bristol-Myers Squibb for providing an educational grant in support of this activity. Engineering the Immune System to Recognize Myeloma Cells 13
Additional Information Speak to an MMRF Nurse Specialist Call Monday Friday, 9:00 AM 7:00 PM EST 866-603-MMCT (6628) Need information about clinical trials? Go to: myelomatrials.org Join the MMRF CoMMunity Gateway to Share and Connect with other Members of the Myeloma Community Go to: mmrfcommunitygateway.org Engineering the Immune System to Recognize Myeloma Cells 14