Latest Advances in Immunotherapies: CAR T Cells and Beyond David L Porter, MD Director, Blood and Marrow Transplantation and Cellular Therapy Program University of Pennsylvania Health System Abramson Cancer Center
Please note that some of the studies reported in this presentation were published as abstracts only and/or presented at a conference. These data and conclusions are included because expert faculty found them to be important scientific contributions but should be considered to be preliminary until published in a peer-reviewed journal.
Disclosure Information: David L Porter Speaker and members of study team have financial interest due to potential upstream IP and patents and licensure to Novartis COI managed in accordance with University of Pennsylvania policy and oversight Funding support for trials: ACGT, LLS, NCI, Novartis Member, ABIM Hematology Board exam writing committee. Some of the studies discussed were published 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.
Cell-Surface Proteins are Targets for New Therapies CD19 CD20 Id B Cell B Cell CD22 HLADR CD52 Many cancer cells have well characterized surface proteins These proteins can be targeted to kill the cell with: Monoclonal antibody Engineered antibody Immune (T) cells Adapted from Press O, et al. Cancer J Sci Am. 1998:4(suppl 2):s19 s26.
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;18:385-397 Image adapted from Janeway CA, Travers P, Walport M, et al. Immunobiology. 5th ed. New York, NY: Garland Science; 2001:221-293; Scheuermann RH, et al. Leuk Lymphoma. 1995;18:385-397; 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;2001:131-146. Memory B cell (IgG, IgA) Plasma cell (IgG)
Targeting with Chimeric Antigen Receptors Antibody to target a specific protein on cancer cell. Sequences bring and keep protein on the surface of T cell Signals for T cell activation (killing), growth, and survival
Targeting with Chimeric Antigen Receptors Antibody to target a specific protein on cancer cell. Sequences bring and keep protein on the surface of T cell Signals for T cell activation (killing), growth, and survival
Targeting CD19+ CLL with CAR-Modified T cells Gene transfer (lentiviral vector) to stably express CAR on T cells confers novel antigen specificity CAR modified T cells can now recognize and kill CD19+ cells Native TCR T cell CTL019 cell CD19 Dead tumor cell Anti-CD19 CAR construct Tumor cell CAR, chimeric antigen receptor; TCR, T-cell receptor.
Rationale for Targeted Cellular Therapy Ultimately, targeted cellular immunotherapy could overcome many limitations of conventional chemotherapy and other forms of adoptive immunotherapy Genetically modified, autologous T cells with redirected specificity to tumor antigens may combine advantages of: Antibody therapy (specificity) Cellular therapy (amplified response) Vaccine therapy (memory activity)
CARs Meet Leukemia (Aug 2017) 335 CTL019 Recipients CLL: 69 adults ALL: 206 (kids and adult) NHL: 43 adults MM 14 adults Other CARs 83
Chronic Lymphocytic Leukemia CLL is cancer of white blood cells or B lymphocytes Usually chronic or slow growing but can be aggressive and life threating Results in accumulation of the malignant B cells. The CLL cells are largely ineffective (incompetent). Abnormal growth and accumulation of mature looking lymphocytes (B cells)
CD19+ CLL: Rationale for Novel Therapies Median survival variable (2 - >20 yrs) Prognosis predictable based on many factors including cytogenetics, numerous biomarkers, and response to therapy Patients with multiply relapsed or refractory disease or high risk features have poor prognosis Incurable except by allogeneic BMT/SCT Associated with extensive morbidity and mortality Many patients not eligible (advanced dz, age, comorbidity, etc.) Newer, more effective therapies for advanced and high risk CLL are necessary
Proportion Surviving Median OS of fludarabine-refractory CLL is 10 months 1.0 0.8 0.6 0.4 0.2 0.0 0 12 24 36 48 60 72 84 96 Months Brown J R Hematology 2011;2011:110-118, from Keating et al, 2002 Leuk Lymphoma 43:1755 1762 2011 by American Society of Hematology
CLL Pilot Study Design and Considerations Single center pilot trial of CTL019 (formally CART19) cells Primary objective: Safety, feasibility and immunogenicity of CTL019 in patients with CD19+ leukemia and lymphoma Detailed inclusion/exclusion at clinicaltrials.gov (NCT01029366) CD19+ B cell malignancies with no available curative options (such as autologous or allogeneic SCT) CLL: failed >2 prior therapies, progression within 2 years of last treatment. Limited prognosis (<2 year) with available therapies.
Overview of CTL019 Therapy 7-14 days
CTL019 Pt 01, Aug 2010 59M, stage IV CLL, 46 XY 7 prior therapies, chemotherapy resistant No standard options available Received lymphodepleting chemotherapy fludarabine/cyclophosphamide. Treated with CTL019 8/3/10. Course complicated beginning 10 day after infusion by high fevers (pneumonia?), hypoxia, hypotension. Critically ill requiring ICU care. Symptoms lasted ~14 days.
CTL019 Pt 01, Aug 2010 Normalization of blood counts Bone marrow without leukemia including flow cytometry and negative IgH PCR CT scans with resolution of enlarged lymph nodes. Achieved COMPLETE REMISSION by day 31 CTL019 cells expanded 1000-10,000x CTL019 cell detectable at >60 mo. CR sustained > 6 years
CTL019 Study Status: subject #2 64M, stage IV CLL, (p53 del) since 2002 4 prior therapies, chemotherapy resistant CART-19 infusion on 9/14/2010 Day 14-19 fevers>102 with rigors, diaphoresis, anorexia, nausea and diarrhea. Hospitalized on day 21 with delayed onset tumor lysis syndrome (TLS). Kidney damage Electrolyte abnormalities Treated appropriately with resolution of abnormalities. Day 31: No evidence of leukemia by any measure
UPN02 Marrow Response by Day 31 Pre-infusions marrow: >50% involved by CLL (40x) Day 31 No evidence CLL and negative by flow cytometry, cytogenetics, FISH or deep sequencing Porter et al. NEJM, 2011
Subject 2 Achieves Complete Remission by Day 31
CD5 CAR19 Rapid expansion of CART cells, rapid eradication of CLL D+1 D+6 D+8 D+10 D+28 CD19 0% 2.5% 58.5% 78.5% 25.4% PDCS CD8 UPCC04409-09 Eurasian Hematology Congress JJ Melenhorst, PhD 10/17/2014 CARs for CLL
CD20 CAR19 CART-19 Persistence and B cell Aplasia Month 12 BM Month 15 PB Month 18 PB Year 3 PB Year 5.5 PB CD3 CD19
Clinical Responses: Bulky Tumor Eradicated Following CART19 Infusion Patient Total Baseline Tumor Burden Response # cells tumor mass (pounds) UPN 01 2.51E+12 5.52 CR (+48 months) UPN 02 3.48E+12 7.67 PR (4 months) UPN 03 1.32E+12 2.90 CR (+48 months) Porter et al. NEJM, 2011 Kalos et al. Sci Trans Med 2011
CLL: Overall Response to CTL019 Response N % Complete Response 11/43 26% Partial Response 10/43 23% Overall Response 21/43 49% unpublished
CART19 (CTL019) Cells For Relapsed, Refractory ALL Structure of a Lenti-virus Lenti-viruses used for T-cell transduction Transduced T-cell attacks a tumor cell
ALL: Rationale for Novel Therapies Prognosis for relapsed or refractory ALL poor Median survival < 1yr 3 yr survival <25% Allogeneic SCT for refractory ALL largely ineffective There is a desperate need for newer, more effective therapies for advanced and high risk ALL.
Outcomes for Adults with 1 st Relapse ALL Male vs Female Age <20, 20-34, 35-49, 50+ Time to relapse >6 mo, 6-12 mo, 1-2 yr, >2 yr +/- Extramedullary disease Relapse after chemo, auto, allo Fielding A K et al. Blood 2007;109:944-950. ECOG 2993
CTL019 for Relapsed Refractory ALL N=30 (evaluable) 25 pediatric and 5 adult patients 40% female, 60% male Median age 14 (5-61) Disease status Primary refractory 10% 1 st relapse 17% >2 nd relapse 73%
ALL: Overall Response to CTL019 Response N=30 % Complete Response 27/30 90% No response 3/30 10% Not evaluable (extramedullary dz (1) and short f/u (4) 5 Maude SL, Frey N. et al. N Engl J Med 2014;371:1507-1517.
ALL (04409-23), Pre-infusion ALL (04409-23), Day 27 Four induction attempts: 10% blasts Photos courtesy of Adam Bagg, MD and Carlos Villa, MD Complete Remission
CAR T cells for ALL: Broader Access Global, multicenter trial ELIANA is a single arm global study with centralized manufacturing of tisagenlecleucel 25 sites in 11 countries across North America, Europe, Australia, and Asia FPFV=8 APR 2015 Data cutoff: 23 NOV 2016
CAR T cells for ALL: Broader Access (Grupp et al, ASH 2016, abstract 22) ELIANA: first global multi-center CAR T cell trial: Pediatric ALL Industrial cell processing of CTL019 therapy US manufactured cell therapy with global supply and chain of custody 25 centers across 11 countries (US, EU, Canada, Australia, Japan) Site training program: logistics and patient management Most pts received CTL019 in timely manner (~ 94% success) Toxicity (CRS) manageable with no deaths due to CRS Efficacy Maintained: CR/CRi 82% All CRs were MRD negative Led to FDA approval of CTL019 (tisagenlecleucel, Kymriah) Aug 30, 2017.
F.D.A. Approves First Gene-Altering Leukemia Treatment (Aug 30, 2017). Flash Mob!
CTL019 For Relapsed Refractory NHL: JULIET JULIET is a global clinical trial with centralized manufacturing of CTL019 27 sites in 10 countries across North America, Europe, Australia, and Asia * * * Manufacturing sites
Primary Endpoint Was Met Response Rate Best overall response (CR + PR) 59% CR 43% PR 16% SD 12% PD 24% Patients (N = 51) a P <.0001 b (95% CI, 44-72) Overall response rate (CR + PR) at 3 months 45% CR 37% PR 8% a The interim analysis was preplanned to include the first 51 patients treated with CTL019 and followed for at least 3 months or discontinued early. b Null hypothesis of ORR 20%; the one-sided p-value threshold to reject the null hypothesis is 0.0047 (O Brien-Fleming boundary) at the interim analysis and 0.0235 at the primary analysis. JULIET ICML 2017
Axi-cel (Yescarta) Pivotal Trial: Response Rates and Toxicity Best Overall Response in Patients with 3 Month Follow-up, med follow up 15.4 mo Subgroup n ORR CR 15.4 mo ORR 15.4 mo CR DLBCL 77 82%* 49% 42% 41% Grade 3 Adverse Events, total N = 93 treated n (%) Cytokine release syndrome 12 (13) Neurologic event 27 (28) Fatal events (excluding PD) 3 (3) Neelapu et al, NEJM 377;26, 2017 Neelapu & Locke et al Feb 28 (Kite)
F.D.A. Approves Second Gene-Altering Treatment for Cancer. By DENISE GRADY OCT. 18, 2017 Axicabtagene Ciloleucel (Yescarta)
Summary: CTL019 for B cell malignancies A living drug that undergoes massive expansion (1000 10,000 fold in vivo) Eradication of large tumor mass (2.5-7 lbs) Overall response rate for CLL 49%, NHL ~60% Overall CR rate for ALL (90%) Cells persist for >60 months after a single treatment Persisting cells remain functional Many potential severe side effects still to be studied. Managed with targeted anti-cytokine therapy CAR therapy holds great promise for patients with advanced, relapsed and/or refractory CLL, ALL, NHL, MM and potentially many other tumors 2 gene modified cell therapy products are now FDA approved to treat cancer!
CAR T Cells for cancer: where are we? TBN TBN AML CLL NHL ALL MM TBN
Colleagues and Collaborators (too many to list) ACC Translational Research Carl June Michael Milone Carmine Carpenito Anne Chew Lester Lledo Elizabeth Veloso Joan Gilmore Holly McConville James Capobiancci Amy Marshall Susan Metzger Penn Clinical Group Noelle Frey* Elizabeth Hexner Saar Gill Steve Schuster Ed Stadtmauer Alison Loren Sunita Nasta Jacob Svoboda Selina Luger Adam Cohen Al Garfall CVPF Bruce Levine Suzette Arostegui Andrea Brennan Andrew Fesnak Eva Henry Anne Lamontagne Lauren Lewitt Alex Malykhin January Salas McKee Matt O Rourke Juliana Rojas Megan Davis Suhoski Clare Taylor Stem Cell Lab and Apheresis Don Seigel Mary Sell Nicole Aqui TCSL DSMC Members Jos Melenhorst Simon Lacey Michael Kalos Joe Fraietta Ed Pequignot Jeff Finklestein Farzana Nazimuddin, Chelsie Bartozak David Ambrose Irina Kulikovskaya, Minnal Fang Chen Vanessa Gonzalez Yolanda Mehnke Saar Gill Marco Ruella Saad Kendarian Study Participants Adaptive TcR, Inc Path./Lab. Med. Adam Bagg Pediatrics Stephan Grupp Shannon Maude David Barrett David Teachey Radiology Sharyn Katz Novartis CTL019 Development Team Novartis
Future CAR T cells: ASCO 2020 Will be routine for B cell malignancies Will target multiple tumor types Will have a defined product composition based on T cell function and phenotype (Tcm?) Will have on and off switches Some will be recognizable Some will not
Targeting with a Chimeric Antigen Receptor 5 LTR y scfv hinge co-stim z 3 LTR Antibody SIGNAL 2 co-stimulatory molecule TCR zeta chain SIGNAL 1 Slide courtesy of C Bollard
Ongoing and Delayed Response in Pt UPN-18 Baseline Month 2 BM and blood NED Month 3 BM and blood NED 10 prior therapies, transformed CLL, del(17p), ibrutinib resistant, XRT resistant