Cellular Immunotherapy for Lymphoid Malignancies

Transcription

1 Cellular Immunotherapy for Lymphoid Malignancies Edward A. Stadtmauer, MD Chief, Hematologic Malignancies Section Professor of Medicine Patricia Mangan, RN, MSN, CRNP Lead Nurse, Hematologic Malignancies/BMT University of Pennsylvania Abramson Cancer Center Philadelphia, Pa Please note that some of the studies reported in this presentation were presented as an abstract and/or presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal. Hematologic Malignancies Update January 26, 2018

2 Immunotherapy for Lymphiod Malignancies: Targets and Tools ADCs GSK Neri et al, Clin Can Res 2016

3 Adoptive T cell therapy (three major approaches) June et al Sci Trans Med 2015

4 CD19: An Ideal Tumor Target in B-Cell Malignancies CD19 expression is generally restricted to B cells and B cell precursors 1 CD19 is not expressed on hematopoietic stem cells 1 CD19 is expressed by most B-cell malignancies 1 CLL, B-ALL, DLBCL, FL, MCL 1 Antibodies against CD19 inhibit tumor cell growth preb-all B cell lymphomas and leukemias CD19 expression Hematopoietic stem cell Pro-B Pre-B Immature Mature Activated (IgM) (IgM, IgD) B cell 1. Scheuermann RH, et al. Leuk Lymphoma. 1995;18: Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001: ; Scheuermann RH, et al. Leuk Lymphoma. 1995;18: ; and Feldman M, Marini JC. Cell cooperation in the antibody response. In: Roitt I, Brostoff J, Male D, eds. Immunology. 6th ed. Maryland Heights, Missouri: Mosby;2001: Memory B cell (IgG, IgA) Plasma cell (IgG)

5 Anatomy of a Chimeric Antigen Receptor (CAR) Gill S, June C Immunol Rev Jan;263(1):68-89 A single-chain variable fragment (scfv) is not actually a fragment of an antibody, but instead is a fusion protein of the variable regions of the heavy and light chains of immunoglobulins, connected with a short linker peptide

6 2nd Generation CAR for B Cell Malignancy: Autologous T Cells Transduced w/ Anti-CD19 Receptor Spliced to CD3 zeta and 4-1BB Signaling Domains 4-1BB 4-1BB Lentiviral vector to deliver construct CD3-z and 4-1BB signaling domains augments proliferation and survival Anti-CD3/anti-CD28 mab coated bead stimulation (artificial DC) CARs directed against CD19 have been tested in CLL and ALL

7 CART19 (tisagenlecleucel-t ): Penn Med Overview Porter, 2011 Grupp, 2013 Maude, 2014 Garfall, 2015 Patient Donates Cells July 31, st CART19 Infusion 7 yrs ago (CLL) Pediatric Oncology: ALL Cytokine Release Syndrome 5 yr ago (ALL) T cell transfusion Adult Oncology: ALL, CLL, DLBCL, MCL, Myeloma Genetic engineering Synthetic Biology Expand T cells CVPF 3 years 4 ago (MM) Slide courtesy of Carl June

8 CD19-targeted CAR T cells for B cell malignancies Experience from numerous national and international trials autologous and allogeneic T cells Responses seen in heavily-pretreated CLL, ALL, and B-cell NHL ORR 40-50% in CLL, 80% in ALL, 50-80% in NHL some durable CRs > 5 years Summary of CTL019 Efficacy in R/R ALL (n = 51) 39 Pediatric and 12 Adult FDA Breakthrough Designation for ALL Maude, et al, NEJM 2014 Davila et al, Science Trans Med 2014; Porter et al, ASH 2013; #873; Maus et al, Blood 2014,

9 F.D.A. Approves First Gene-Altering Leukemia Treatment, Costing $475,000 R/R ALL (age <25 yr) CD19 Directed CAR New York Times, 8/30/2017

10 Flash Mob at Penn Medicine FDA Approval CAR T

11 F.D.A. Approves Second Gene-Altering Treatment Yescarta, Kite Pharma (R/R NHL) CD19 Directed CAR New York Times, 10/18/2017

12 But not without toxicity On target toxicities: Tumor lysis syndrome B cell aplasia hypogammaglobulinemia Off target toxicities: Cytokine release syndrome persistent high fevers, rigors, myalgias, hypotension, hypoxia, neurologic dysfunction, HLH/macrophage activation syndrome very high IL6, also IFN-gamma, TNF responds to steroids but lose CAR T cells tocilizumab (anti-il6 receptor mab) can abrogate CRS CNS toxicity The causative pathophysiology of these neurologic side effects is unknown, though given similar events reported with blinatumomab administration The neurologic toxicity has been reversible in a majority of cases Bonifant et al, Molecular Therapy Oncolytics (2016) 3, 16011;

13 CAR T Therapy is Complicated and Expensive Is the Juice Worth the Squeeze? CAR T therapy vs Chemotherapy for R/R ALL If there is a cure, its worth it! Hettle R et al. Health technology assessment (Winchester, England). 2017;21(7):

14 The Process takes sophisticated and extensive organization and coordination (modified from Kite Presentation) Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Expanding beyond The Trial Setting Community & Patient Management Centers of Excellence

15 Site Selection Activation & Site Preparation Patient ID& Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Clinical Setting Identify potential sites through 1:1 meetings Identify primary clinicians Feasibility assessment Contracting Site initiation visit (SIV) including Dry run Training on the product manual 15 15

16 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Cadence to Readiness Practice Dry Run Authorized site listed on website Schedule and execute Institution Kick Off Meeting Functional Meetings Quality Audits Bill set up Training preparation etc Institution Training & Certification Quality training Product training - Prescribing Information - REMS - AE Guide REMS Assessment and Enrollment Multiple small group meetings to identify champion 16

17 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Central Manufacturing Process Conditioning Dosing & Patient Monitoring Clinical Setting Patient Identification Indication and limitation of use Physicians clinical judgement Medical Affairs response to unsolicited questions Enrollment Automated system available on line or by phone Patient enrolled before apheresis For the Kite Product Relapsed and Refractory B-cell Lymphoma after 2 prior lines of therapy E.g. DLCL after R-CHOP with relapse and then RICE-> ASCT now with relapse For Novartis Product Relapsed and Refractory childhood B- ALL Age < 25 E.g. after AYA induction protocol with relapse after allosct now with relapse Data on File, Kite Pharma in collaboration with Penn Medicine 17 17

18 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing A ph Conditioning e A r e s i s Dosing & Patient Monitoring Site training Apheresis conducted per institutional guidelines Examples of apheresis instruments: COBE Spectra Apheresis System Fenwal Amicus Separator Spectra Optia Apheresis System Data on File, Kite Pharma in collaboration with Penn Medicine 18 18

19 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning M Dosing an & u Patient f a c t u r i n g Monitoring Roberts et al

20 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Integrated Delivery START PENN Apheresis END PENN Infusion Kite Manufacturing Integration Across Kite Patient scheduling Chain of Identity/Chain of Custody Courier shipment tracking Portal for hospitals Data on File, Kite Pharma in collaboration with Penn Medicine

21 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Consistent throughout trial setting and into clinical setting Lympho-depleting chemotherapy of cyclophosphamide 500 mg/m 2 IV and fludarabine 30 mg/m 2 IV Administered on the fifth, forth, and third day before infusion of anti-cd19 CAR T cells Data on File, Kite Pharma in collaboration with Penn Medicine 21 21

22 Site Selection Activation & Site Preparation Patient ID & Enrollment Apheresis Manufacturing Conditioning Dosing & Patient Monitoring Clinical Setting Anti-CD19 CAR T cells administered at Hospital of the University of Pennsylvania Guidance on monitoring patients provided in the Prescribing Information and REMs documents Information on AEs and guidance on treatment for CRS and neurotoxicity in the Prescribing Information and REMs documents AEs and product complaints collected through Medical Information. Data on File, Kite Pharma in collaboration with Penn Medicine 22 22

23 Scheduling and coordination Cell collection, pheresis IT, HIPPA Pharmacy Consult services (neuro, renal ) APPs Ins. approval Inpatient Units Patient ICU Billing Outpatient units Faculty, fellows, residents Emergency Dep t Global Medicine Social services, housing Data reporting (mandatory) Cell Manufacturing Laboratory assessment

24 Conclusions We have now treated over 350 patients with genetically modified T cell therapy B Cell ALL B Cell NHL Multiple Myeloma Mesothelioma Ovarian Cancer Now FDA approval and commercial use of CD19 directed T-cells for ALL and NHL The ERA of cellular immunotherapy for cancer is here and Penn Medicine is at the center of the revolution Contact Information David Porter, MD, Director, Cellular Therapy Program Elizabeth Weber, RN, Coordinator, Cellular Therapy Refer prospective patients to the disease oriented physicians who will then assess and refer for cellular therapy if indicated 24

25 Acknowledgements Principle Investigators Adam Cohen Alfred Garfall Edward Stadtmauer Carl June Penn Myeloma/BMT Dan Vogl Brendan Weiss Patricia Mangan Emilie Tilhou Colleen Erb Mary Sanchez Tim Holtz Kelly Kraus Kathy Cunningham Funding Novartis, Adaptimmune Leukemia & Lymphoma Society NIH: K12 CA The Parker Institute Heme/Onc Division David Porter Noelle Frey Lynn Schuchter Alison Loren Steve Schuster Jakub Svoboda ACC TRP Karen Dengel Naseem Kerr Holly McConneville Elizabeth Veloso Lester Lledo Anne Chew TOO NUMEROUS TO PUT ON SLIDE CCI Jos Melenhorst Simon Lacey Yolanda Mahnke Chris Carlson Nina Luning Prak Martin Carroll Mike Malone CVPF Bruce L. Levine Zoe Zheng Julio Cotte Dawn Meier Alexey Bersenev Special Thanks To: THE PATIENTS AND THEIR FAMILIES THE INPATIENT AND OUTPATIENT NURSING STAFF, REFERRING MDs THE MYELOMA AND CELLULAR IMMUNOTHERAPY COMMUNITY ACC Pilot funds : Heme Malignancies TCE, GREG WOLF Foundation ACC Shared Resources (Human immunology Core, CRU, Biostatistics, etc) U Maryland Aaron Rapoport Ashraf Z. Badros Saul Yanovich Gorgun Akpek Sunita Phillips Kelly-Marie Betts Phillip Miller Sandra Westphal Adaptimmune Gwen K Binder-Scholl Bent K Jakobsen Dominic P Smethurst Helen K Tayton-Martin Joanna E Brewer Alan D Bennett Andrew B Gerry Nick J Pumphrey Lilliam Ribeiro