Hematopoietic Cell Transplantation: Evolution, Current and Future State

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1 Hematopoietic Cell Transplantation: Evolution, Current and Future State Stephen J. Forman, MD Chair Department of Hematology/ Hematopoietic Cell Transplantation Director Hematologic Malignancies and Stem Cell Transplant Institute City of Hope Comprehensive Cancer Center

2 DISCLOSURES Grant/Research Support, Consultant and Stock/Shareholder for Mustang Bio

3 Goals To review evolution of stem cell source and applications of stem cell transplant in the treatment of hematologic malignancy. To highlight some of the evolving treatment strategies to improve outcomes after transplant. Impact of novel therapies on transplant strategies: CAR T cells

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5 City of Hope HCT Program since 1976 Ernest Buetler ( ) Karl Blume ( )

6 Indication for Transplants 1977 Acute Leukemia Aplastic Anemia Types of Marrow/Stem Cell Transplants 1977 Bone marrow from Sibling Donors

7 Indications for Transplant 2019 Hematologic Malignancy: Solid Tumor Malignancy: Leukemia (ALL, AML, CML, CLL) Lymphoma Hodgkin Lymphoma Myeloma Testicular Sarcoma Brain Neuroblastoma Myelodysplasia Myeloproliferative Disorder

8 Indications for Transplant 2019 (Cont d.) Acquired Non-Malignant Disease: Aplastic Anemia Amyloid Autoimmune diseases: Scleroderma Inherited Non-Malignant Disease: Sickle Cell Thalassemia Severe Combined Immune Deficiency Osteopetrosis Multiple Sclerosis Granulocyte & Macrophage Disorder Fanconi s Anemia

9 Types of Marrow/Stem Cell Transplants Allogeneic sibling matched donor 2. Allogeneic parental matched donor 3. Allogeneic unrelated matched donor 4. Allogeneic haploidentical matched donor (parents, sibling) 5. Syngeneic (twins) 8. Autologous peripheral blood stem cell 9. Allogeneic peripheral blood stem cell 10. Allogeneic donor leukocyte infusion 11. Gene modified stem cells: ADA deficiency Gaucher AIDS 12. Ex vivo expanded stem cells 6. Cord blood 13. T cell depleted allogeneic 7. Autologous marrow

10 Likelihood of Finding an 8/8 HLA Match by Year End, Based on Current Donor Availability and with Recruitment Trends Extended to Gragert L et al. N Engl J Med 2014;371:

11 Allogeneic HCT Recipients in US by Donor Type

12 Bone-Marrow Ablation and Allogeneic Marrow Transplantation in Acute Leukemia Thirty-three patients with acute leukemia (15 with lymphoblastic leukemia and 18 with myeloblastic leukemia) were entered into a program of high-dose radiochemotherapy followed by allogeneic bone marrow transplantation. These patients were in various clinical stages of disease. Of 10 in complete hematologic remission at the time of transplantation, seven were alive without maintenance therapy at the time of evaluation, eight to 35 months after grafting; one was in relapse. Of 11 who received transplants during partial remission, six were in remission without further treatment eight to 33 months after transplantation. In 12 the disease was refractory to chemotherapy when preparation for transplantation was started, and only one of them was alive and free of disease after 10 months. Recurrent leukemia, graft-versus-host disease, viral pneumonia, and early therapy-related toxicity were the major causes of failure. High-dose chemotherapy and total-body irradiation followed by allogeneic marrow transplantation performed during complete or partial remission can produce long term remission of acute leukemia. Karl G. Blume, M.D., Ernest Beutler, M.D., Klaus J. Bross, M.D., Ram K. Chillar, M.D., Owen B. Ellington, M.D., John L. Fahey, M.D., Mark J. Farbstein, M.D., Stephen J. Forman, M.D., Gerhard M. Schmidt, M.D., Edward P. Scott, M.D., Wayne E. Spruce, M.D., M. Ann Turner, M.D., and Jeffrey L. Wolf, M.D. N Engl J Med 1980; 302: May 8, 1980

13 Figure 1 Survival analysis of 33 patients entered into City of Hope Bone Marrow Transplantation Program between May 1976 and May 1979

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15 CMV IP

16 CMV infection and disease post-hsct Pre-antiviral Era CMV CMV Disease CMV infection occurred at a median of ~43 days by culture/ag but median of 33 days by serum DNA PCR assay Disease occurred at a median of 53 days Risks associated with GVHD, lymphopenia, older age, sero-positivity of recipient, pre-treatment chemotherapy, post-treatment immunosuppression T cell immunity recognized as an important factor in disease

17 Treatment of CMV IP Authors: Gerhard M. Schmidt, Andrea Kovacs, John A. Zaia, Karl G. Blume, Auayporn P. Nademanee, Margaret R. O Donnell, David S. Snyder Stephen J. Forman

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19 First Method for Preemptive Use of GCV

20 CMV in allogeneic HCT - Early CMV reactivation remains a significant cause of morbidity/mortality in HCT recipients. - Pre-emptive antiviral drugs reduced mortality from CMV pneumonia, but with limitations; Delayed immune reconstitution/late CMV disease Toxic side effects: myelosuppression, renal dysfunction High costs - Prophylactic approaches: letermovir Late CMV reactivation Immune reconstitution? Cost, poly-pharmacy Vaccine approaches to improve immune reconstitution

21 CMV Research at COH 1984: Cloning of pp65 Zaia, Riggs; PNAS : Identification of pp65 as a main immune target Forman SJ, et al.j Immunol McLaughlin-Taylor E, et al. J Med Virol : Landmark study demonstrating survival advantage of Pts treated with preemptive GCV Schmidt, et al. N Engl J Med Goodrich JM et al. N Engl J Med : Identification of an HLA-A0201-restricted immundominant epitope, pp Diamond et al. Blood 1997

22 CMVPepVax

23 CMVPepVax in HCT recipients Objectives: to evaluate safety and immunogenicity Lancet Haematol Feb;3(2):e87-98.

24 Study Design Randomized, open-label, pilot phase Ib trial CMVPepVax Arm (n=18) and Observation Arm (n=18) stratified by donor serostatus Recipients: HLA-A*0201, CMV seropositive, Matched donor HCT, no ATG HCT Eligibility screening Eligibility for vaccination Follow up visits for clinical assessments Day -60/ Vaccine injection Immunologic monitoring by HLA-A2 pentamers

25 Enrollment/Randomization N=46 Enrolled pre- HCT N=36 Randomized N=10 Ineligible for randomization Day 28 eligibility check Steroid dosage: 1 Grade 3 GVHD: 2 Ongoing grade>3 AEs: 3 Patient withdrew : 3 Death: 1 N=18 Vaccine Arm* N=18 Observation Arm Follow up: 34 patients > 100d (safety/cmv endpoints) 31 patients >180d (immunologic endpoints) *Four patients did not receive d56 vaccinations due to the use of anti-cmv drug (n=2), self-decline (n=1), or ongoing grade 3 toxicity (n=1)

26 Cumulative incidence CMV Viremia Lancet Haematol Feb;3(2):e87-98 Days post-hct

27 HIV gag CMV pp65 pp65 specific CD8 T cell Response d28 CMVPepVax d56 CMVPepVax pre HCT d42 d70 d100 d180 CD8 HLA-A2 pentamer binding assay in Vaccine Arm UPN 8

28 Relapse-free Survival Lancet Haematol Feb;3(2):e87-98

29 Summary of CMV Pepvax Safe and well-tolerated in HCT recipients Associated with reduced viremia Possible benefit in survival? Accompanied by an increase in CMV-specific T cells dominant TEM/TEMRA phenotypes in the epitope specific CD8 T cells variability in the proportions of TEM/TEMRA in response to pp65 and IE1 library stimulation Multi-center phase II trial underway UMN (Rashidi) FHCRC (Hill), Ohio (Choe), Emory (Waller)

30 Cancer Immunotherapy: Empowering the T cells for Cancer Eradication Cancer Vaccines: Educate/boost endogenous T cell immune responses First FDA-approved cancer vaccine: Provenge for treatment of metastatic castrate-resistant prostate cancer Tumor cell MHC TCR T cell Immune checkpoint inhibitors: Activate/stimulate endogenous T cell immune responses CTLA-4 blockade (Ipilimumab) PD-1/PD-L1 blockade (Nivolumab/Pembrolizumab) Tumor cell MHC TCR PD1 T cell Nivo/Pembro T cell therapy: Engineer NEW T cell immune responses Chimeric Antigen Receptor (CAR)- engineered T cells Tumor cell CD19 T cell T Cell Receptor (TCR)-engineered T cells

31 Adoptive Therapy Using CAR-Engineered T cells 1. Collect T cells 5. Infuse 2. Activate 4. Expand 3. Engineer

32 CAR-Engineered T cells Eliminate Cancer Cells T cells + Brain Tumor Cells Engineered CAR T cells + Brain Tumor

33 Challenges in CAR T cell Therapy - Short T cell persistence - Excessive T cell exhaustion from prolonged growth ex vivo. - Inability to re-stimulate T cells after relapse Properties of CMV-specific T cells - Life-long persistence - Recovery after HCT despite use of immunosuppressive agents - High frequency of memory T cells - Potent - Track record on Adoptive T cell therapy - Available vaccine for in-vivo stimulation via endogenous TCR

34 CD19-CAR T cells for B-cell Malignancies Leslie Popplewell, MD Tanya Siddiqi, MD Samer Khaled, MD Elizabeth Budde, M.D., Ph.D.

35 CAR T Cell for Adult ALL 13 Patients 100% complete remission 100% MRD Negative No grade 4 CRS or neurotoxicity Bridge to allogeneic transplantation Combine CAR T cells with transplant

36 CD19-CAR T cells Mediate Potent Antitumor Activity Against Non-Hodgkin Lymphoma Case Report #2: 61 yr; male Relapse high-grade B cell lymphoma Lymphodepletion: Flu/Cy CD19:28ζ CAR T cells (200M) Grade 2 CRS (1x toci); no neurotoxicity Day -17 Day +34

37 Rituximab maintenance after Auto HCT in relapsed DLBCL: CORAL Study Gisselbrecht et al, J Clin Oncol 2012

38 City of Hope Relapse Free Survival after Autologous HCT for DLBCL, Patients at Risk Time (years) RR SR

39 City of Hope Relapse after Autologous HCT for DLBCL, p-value: Patients at Risk Time (years) RR N/A SR

40 Autologous HCT Plus CD19 CAR T Cells Phase I Studies of Cellular Immunotherapy Using Central Memory Derived-CD19-Specific T Cells Following Autologous Stem Cell Transplantation for Patients with High- Risk Intermediate Grade B-Lineage Non-Hodgkin Lymphoma Leslie Popplewell**, MD 1, Xiuli Wang**, PhD 1, Araceli Naranjo, BS 1*, Suzette Blanchard, PhD 2*, Jamie Wagner, BS 1*, ChingLam Wong, BS 1*, Ryan Urak, MS 1*, Wen-Chung Chang, MS 1*, Samer K Khaled, MD 3, Tanya Siddiqi, MD 1, Elizabeth E. Budde, MD, PhD 1, Jingying Xu, PhD 1*, Brenda Chang, BS 1*, Sandra H. Thomas, PhD 1, Laurence J. N. Cooper, MD. PhD, Stanley R. Riddell, MD 4*, Christine Brown, PhD 1*, Michael C Jensen***, MD 5* and Stephen J. Forman***, MD 1

41 Phase I Clinical Trial Using CD19:28ζ-CAR Tn/mem cells Following Autologous Stem Cell Transplant Leslie Popplewell, M.D.; Clinical PI Enrollment: Relapsed or high-risk B Cell Lymphoma (recurrent large cell & mantle cell lymphoma) High risk patient population for relapse with poor prognosis with auto-transplant Clinical Design: Infuse cells on day +2/+3 after HSCT Lymphopenic environment to support homeostatic expansion Engraft cells as a component of the reconstituted immune system

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43 CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells Xiuli Wang, ChingLam W. Wong, Ryan Urak, Armen Mardiros, Lihua E. Budde, Wen-Chung Chang, Sandra H. Thomas, Christine E. Brown, Corinna La Rosa, Don J. Diamond, Michael C. Jensen, Ryotaro Nakamura, John A. Zaia, Stephen J. Forman Clin Cancer Res Jul 1;21(13):

44 Application of CMV immunology and vaccine for CAR T cell therapy

45 Improved anti-lymphoma efficacy of adoptively transferred CMVxCD19CAR bi-specific T cells by CMV vaccine Day: Untreated Euthanized CMV-specific T CM pp65 vaccine Euthanized Prior Vaccine Post CMVxCD19CAR T CM pp65 vaccine CMVxCD19CAR T CM mp1 vaccine Scale 5e3-5e4 5e4-5e5 5e5-5e6 5e6-5e7 Day -3: 1x10^6 CD19 + LCLffluc Day 0: 10X10^6 CMVxCD19CAR+ T cells Day18: irradiated 5x10^6 pp65 peptide/mp1peptide pulsed T cells (T-APC)

46 Clinical Translation Overview Transduce our current CD19-CAR T cell construct into T cells (autologous or allogeneic) that have been selected for cytomegalovirus (CMV) specificity. Use a CMV-MVA vaccine to further expand the CMV/CD19 bi-specific T cells in vivo. This sequential therapy will be applied pre-emptively after either autologous or allogeneic HCT for high-risk CD19+NHL, ALL

47 Planned auto/allo HCT trials for CD19+NHL Planned cell dose: 10-20x10 6 Supported by Lymphoma SPORE Leukemia trials: Pending LLS, R01 CMV-HIV CAR: supported by CIRM

48 COH T Cell Therapy Research Program

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