T-Receptor Modified Immune Therapy is Better Than Conventional DLI

Transcription

1 T-Receptor Modified Immune Therapy is Better Than Conventional DLI David L Porter, MD University of Pennsylvania Medical Center Abramson Cancer Center COSTEM, Berlin 10/13/13

2 Relapse After Allogeneic SCT: Background Relapse after allogeneic SCT has a very poor prognosis. GVL activity of allogeneic SCT well established GVL induction with DLI is dramatically effective for relapsed CML DLI has limited activity for relapsed AML, MDS or ALL. DLI has modest benefit for relapse of other diseases and outcomes poorly defined for relapsed CLL, NHL.

3 DLI only for AML: Selected Trials Ref N= CR Comments Collins, /39 (15%) OS <20% Kolb, /17 (29%) Med survival 248d all AML/MDS pts Shiobara,BMT /21 (38%) 7% OS at 2 yrs Levine, /57 (47%) Chemo/DLI 2 yr OS 19% Schmid, % 2 yr OS 21%

4 DLI for AML yr survival 1 yr EFS CR: 51% 34% No response: 5% 0% 2 year survival 19% (95% CI 11-33%) Years After DLI Levine, et al; JCO 20:405, 2002

5 DLI (+ Chemotherapy) vs no DLI for Relapsed AML Schmid et al (EBMT), JCO 07 DLI 2 yr OS 21% (median 5 mo) Multivariate analysis for OS after relapse age < 37 years (P =.008) longer CR after HSCT (> 5 months; (P <.0001) use of DLI (P =.04). P % ( +2%) 21% ( +3%)

6 Outcomes for Adults with Relapsed MDS Campregher, et al (Seattle) N=16 ( ) Gr II-IV agvhd in 43% cgvhd in 36% CR 3/14 evaluable pts All 3 with gr III-IV agvhd All patients died by 68 mo 9 died w/i 6mo 5 died w/i 20 mo 2 died mo (pulm)

7 DLI is ineffective to treat relapsed ALL after allogeneic SCT

8 Relapsed ALL after Allogeneic SCT Poon et al, 2013 (MDA) Relapse in 123/381 pt between Median age 31 74% prior myeloablative transplant 53% MSD, 37% MUD, 5% mm related donor, 6% UCB 80% systemic relapse, 20% EMD Time to relapse 4 mo (1-38 mo) Poon et al, 2013 (MDA)

9 Outcomes for Adults with Relapsed ALL (Poon et al, BBMT 2013) Treatment N CR % Med OS (mo) Outcome Mild chemo (clo, aza, steroids, TKI..) Intensive chemo (HCVAD, etc) 27 41% 4 TRM 1 Rel 25 Ongoing CR 1 (4%) 30 27% 4 TRM 2 Rel 24 UK 1 Ongoing CR 3 (10%) XRT or IT 6 83% 3 TRM 1 Rel 4 Ongoing CR 1 (17%) DLI + Chemo (mild 3, intensive 8) 2 nd SCT (Chemo mild 5, intensive 14) 11 64% 6.5 TRM 2 Rel 9 Ongoing CR % 10 TRM 5 Rel 8 Ongoing CR 6 (31%)

10 Outcomes for Adults with Relapsed ALL Collins, et al. BMT 2000 n=44, OS 13% (3 pts alive >1yr) Choi, et al. BMT 2005 n=10, CR 7/10 OS 13% (1 pts alive in CR) Poon, et al. BBMT 2013;19, 1064

11 There is limited information on role and outcome of DLI to treat relapsed CLL after allogeneic SCT. Modest activity.

12 Donor Lymphocyte Infusions for Relapsed CLL Study n Preceding chemotherapy CR CD3 Dose Notes Russell None 3 (75%) 2 x 10 7 /kg DLI-induced aplasia 2nd SCT in 14m Ritgen None 7 (78%) ND CCR > 2 years Gribben None 6 (86%) 1 x 10 7 or 3 x 10 7 /kg 50% gr II-IV agvhd or extensive cgvhd Marks None 1 (14%) ND 0% CCR Sorror (20%) 1 x 10 7 to 1.5 x 10 8 /kg 1 PR, no durable response to chemotherapy Khouri rituximab 7 (70%) 1 x 10 7 to 1 x 10 8 /kg 2 PR Planned rituximab Sorror Antibody ND ND Antibody + DLI Delgado none 3 (21%) 1 x 10 6 to 1 x 10 8 /kg 1 PR, 2 died GVHD Hoogendoorn none 5 (45%) unknown OS 67%, EFS 33% at 2 years Overall CR rate is 45% (33/73) Minority have durable responses

13 Except for CML, DLI is ineffective to treat relapse after allogeneic SCT. Safer, more effective therapies are desperately needed.

14 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)

15 Targeted Cellular Therapy for Relapse Several potential lymphoid targets for leukemia-specific T cell therapy identified. Anti-CD19 redirected T cells in clinical trials Targets for relapsed myeloid leukemias poorly defined or not tightly restricted. Discussion regarding CAR modified T cells will be limited to relapse of lymphoid malignancies.

16 CD19: An ideal tumor target CD19 expression is restricted to B cells and possibly follicular dendritic cells CD19 is not expressed on pluripotent bone marrow stem cells CD19 is expressed on the surface of most B cell malignancies Antibodies against CD19 inhibit growth of tumor cells preb-all B cell lymphomas and leukemias myelomas Stem Cell pro B pre B immature B mature B plasma cell CD19 CD22 CD20 Brentjiens / Sadelain

17 Targeting Leukemia with Chimeric Antigen Receptor Modified T cells CARs combine an Ag recognition domain of antibody with intracellular signaling domain into single chimeric protein. Gene transfer (lentivirus vector) to stably express CAR on T cells confers novel Ag specificity. Native TCR T cell CTL019 cell CD19 Dead tumor cell Tumor cell Anti-CD19 CAR construct

18 CARs Meet Leukemia 26 patients with advanced, heavily pre-treated CLL 11 with del17p 1-10 prior tx s 23 patients with relapsed ref ALL (20 evaluable) 18 children 5 adults 14 rel after allo

19 CLL: Pilot Study Demographics N=14 12 men, 2 women Median age 66 (51-78) Prior therapies, median 4 (1-10) P53 deletion, 6/14 Lymphodepleting chemotherapy Bendamustine (6) PC (5) FC (3)

20 CTL019 (CART19) Dose Optimization Trial Randomization between 5 x 10^7 and 5 x 10^8 CTL019 cells 12 patients 28+ days (21 enrolled) Primary endpoint CR by 3 mo Demographics 8 men, 4 women median age 62 (54-78). 4 prior therapies (2-8) P53 deletion 5/12

21 Overall Response of CLL to CTL019 ( ) CR 6/26 (23%) Median f/u 15 mo (5-36 mo) Confirmed by MRD flow and/or deep sequencing PR 6/26 (23%) Median f/u 6 mo (2-12 mo) Major responses 12/26 (46%)

22 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

23 Relapse/Refractor Adult ALL (04409) UPN Chemo CRS? Treat? 23 Clofara Yes Yes 26 MTX/AraC Yes, no tx Comments MRD* neg mo 2 Allo transplant mo 3. GVHD, otherwise well, d100 marrow pending. CR pre infusion No donor options Response CR d60, MRD neg Allo txp 3mo, CR 3 mo after allo. CR at 1 mo (d82) (MRD neg) 27 CVAD No No donor options CR at 1 mo (d55) (MRD neg) 29 Cytoxan Yes Yes MRD negative at mo 1. Declines transplant. CR at 1 mo (MRD neg) 31 Cytoxan Yes No Admit day 2 with T 103 CRP 2.4 to 110 in 24 hrs, CR day 28 (MRD neg) 32 Cytoxan Infusion Sept 17 NE Porter, Frey, unpublished data

24 CTL019 for Relapsed ALL after Allogeneic SCT (CHP959) Response (11 evaluable, 3 follow up too early): CR 8/11 (73%) 7/8 MRD negative (64%) PR/NR 3/11 (27%) Relapse after CR, 3/8 1 CD19- ALL (prior blinatumumab therapy) 1 leukemia cutis with MRD negative marrow Ongoing CR 5/11 (45%) No GVHD Appropriate patient selection with be important Grupp, unpublished data

25 EFS CTL019 for Relapsed ALL After Allogeneic SCT (CHP) Time Grupp, unpublished data

26 Conclusions: CTL019 (CART19) Responses may be vector dependent (not all CARs are the same) CTL019: Can under go massive expansion ,000 fold in vivo Persistence for >36 months. Persisting cells are functional Responding patients develop CRS. Treated effectively with anticytokine therapy Responding pts develop B cell aplasia.

27 Conclusions: CTL019 (CART19) Overall CR rate for relapsed ALL after allogeneic SCT 73% Marked responses in relapsed CLL/MCL Potent activity in relapsed refractory CLL/ALL Overall response rate 12/26 CLL (46%), several PRs ongoing and no pt in CR has relapsed. Overall CR rate 18/21 ALL (86%) 5/5 CR in adults and 13/16 in pediatric pts with 4 relapses 14/20 currently in CR (70%) CAR therapy holds great promise for patients with relapse after allogeneic SCT, particularly with lymphoid malignancies.

28 ANSWERS Is CAR T cell immune therapy better than conventional DLI for all hematologic malignanices? Unknown Need to define appropriate targets for testing Is CAR T-cell immune therapy better than conventional DLI for relapsed CLL? Probably Is CAR T-cell Immune Therapy Better Than Conventional DLI for relapsed ALL YES (and conventional DLI doesn t work) If something does t work, try something else Thomas Edison

29 MEATLOAF Would you use conventional DLI to treat relapsed ALL after allogeneic SCT? RELAPSE

30 Colleagues and collaborators (too many to list) ACC Translational Research Carl June Carmine Carpenito Michael Milone Anne Chew Lester Lledo Elizabeth Veloso Joan Gilmore Holly McConville Univ Penn Clinical Group Noelle Frey Alison Loren Ed Stadtmauer Christina Jemison Selina Luger Steve Schuster Elizabeth Hexner Ran Reshef Sunita Nasta Saar Gill Jacob Svoboda CVPF Bruce Levine Andrea Brennan Anne Chew Ashley Vogel Zoe Zheng MD Anderson CC Laurence Cooper Bipulendu Jena TCSL Michael Kalos Minnal Gupta Irina Kulikovskaya Jeff Finklestein Frazana Nazimuddin Vanessa Gonzalez Saar Gill Adaptive TcR, Inc DSMC Members Study Participants Path./Lab. Med. Adam Bagg Pediatrics Stephan Grupp Shannon Maude David Barrett Radiology Sharyn Katz

31 DLI for Relapse (non-cml) Disease Response Rate AML 15-36% ALL 0-18% MDS 25-40% Myeloma 9-50% NHL 20-60%

32 Pediatric ALL (CHP959) N=18 (16 evaluable) CR 13/16 (81%) Relapse after CR 4 Sustained CR 9/16 (56%) 1 relapsed after prior blinatumumab 14 relapsed after allogeneic SCT No active GVHD Grupp, unpublished data