Outline. Cellular Therapy for Regenerative Medicine (&More): Update of Cellular Therapy Registry. What is Cellular Therapy?

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1 Outline Cellular Therapy for Regenerative Medicine (&More): Update of Cellular Therapy Registry Marcelo C. Pasquini, M, MS What is cellular therapy? Scope: Cellular therapy for regenerative medicine. Cellular therapy related HCT Cellular Therapy Registry Current status ata collection Moving Forward: CARs (Chimeric Antigen Receptors) Co-infusions in HCT New08_1.ppt New08_2.ppt What is Cellular Therapy? Utilization of cells for treatment of human diseases. Transfusion and Hematopoietic cell transplantation (HCT) are cellular therapies. What are the differences? Transfusion terminally differentiated cells that survive in the recipient for a short period of time. HCT stem and progenitor cells engraft and replace the recipient s bone marrow. Terms and efinitions: Potency Totipotency: total potential. Cells able to differentiate all cells in an organism including extraembryonary tissue. Ex: embryonic stem cells. Pluripotency: potential for multiple outcomes. Cells able to originate cells of different lineages. Ex: mesoderm cells. Multipotency: cells able to originate several lineages. Ex: hematopoietic stem cells. Stem Cells Potency Embryonic Stem Cells (ES) Potency 1

2 Terms and efinitions Stem cells: cells able to self renew and differentiate into mature cells (potency). Progenitor cells: similar to stem cells but more limited. Stem Cell Progenitor Cell Self renewal Unlimited Limited Potentiality Multipotent Unipotent, sometimes multipotent Maintenance of Self Renewal Yes No Hematopoiesis Scheme Stem Cells Progenitor Cells Terms and efinitions Terminal differentiation: cells that achieve maximum differential/maturation. Committed cell: maturing cells on a specific lineage path. Transdifferentiation: cells committed to one lineage differentiating into different lineages. Ex: blood cells neurons (???). Induced Pluripotent Cells (ips): terminally differentiated cells induced to become pluripotent with in vitro manipulation. Lineages derived from Human ips cells Takahashi K et al. Cell 2007, 131: Hematopoietic Stem Cell Transplantation - Classification - Allogeneic HLA-identical Other Unrelated sibling relative Syngeneic Autologous onor Autologous Allogeneic Syngeneic Tissue Specific Cellular Therapies - Classification - Single vs. onor Pool ifferentiated Stem cells Progenitor cells Live or cadaveric Manipulated cells (ips) onor Cell Type Myeloablative Reduced Intensity Nonmeyloablative Conditioning Regimen Intensity Bone marrow Peripheral blood Umbilical cord blood Placenta Umbilical cord Amniotic Fluid Cardiac, Skin Liver. Graft Source Bone marrow Peripheral Blood Umbilical cord blood Graft Source Unmanipulated vs. Cell separation Cells in solution tissue engineering Graft manipulation Negative or positive selection Ex vivo expansion In vivo selection Graft manipulation Infusion type IV HLA matching Recipient preparation Other Classifications BAS05_14.ppt BAS05_14.ppt 2

3 Cellular Therapy for Regenerative Medicine Cellular Therapy for Regenerative Medicine Rapidly evolving field with ramifications to most medical specialties Utilize cells for treatment of nonhematologic illnesses Bone marrow derived cells are most commonly used presently. Indications include: cardiovascular, neurological, autoimmune, pulmonary, musculoskeletal among others. Cellular Therapy for Regenerative Medicine Why a cellular therapy registry? Why should the CIBMTR be involved? HCT is a type of cellular therapy. Experience with HCT outcomes research. Experience in developing and maintaning large databases. Many cellular therapies are within the HCT field. Well established infrastructure Network of centers that are starting cellular therapy programs. Nature Reviews SCTO Collect data on outcomes of all allogeneic hematopoietic stem cell transplants in the US Collect data on outcomes of all transplants facilitated by the CW Bill Young Program even if transplant done outside the US Include alternative uses of hematopoietic stem cells Core set of data sufficient to allow center-specific survival and other analyses Subset of Report Form data Establish related donor-recipient specimen repository Cellular Therapy Registry Capture other uses of hematopoietic cells. evelopment of Form 4000 (CTRM). Implement a new data collection track. Update the recipient IS assignment form (CRI form) Allow for any center to register data. Initial phase: Registration only to capture activity. Launched January

4 Single Informed Consent for data collection ata reporting initiation Transplant Center or Cellular Therapy Center CRI Form Form 2804 Form 2804: CIBMTR I Assignment No 1. Conditioning regimen 2. Intent to replace the recipient s hematopoieisis Yes Form 4000 CTRM Pre-TE Form 2400 FormsNet Cardiac Applications for Cellular therapies Indications with largest experience: remains investigational. Treatment for myocardial infarction. Mainly bone marrow derived cells: Unmanipulated, C34+selection, MSC, cardiac progenitor cells. Infusion: intracoronary, intracardiac. Timing: within days from AMI but variable. Promising outcomes: improvement of EF and survival. How does it work? CIBMTR Cellular Therapy for Regenerative Medicine (CTRM) Form 4000: isease indications Other indications being investigating Multiple Sclerosis Crohn s isease and ulcerative colitis Systemic Lupus Erythematous iabetes mellitus type I Rheumatoid Arthritis Avascular Necrosis of the Femur Amiotrophic Lateral Sclerosis Myasthenia gravis Acute cerebral vascular ischemia 4

5 CTRM: isease Indications Cell Products Mostly unmanipulated Selection vs. unselected Mesenchymal stem cells Capacity to differentiate to cartilage bone or fat. From bone marrow or other tissues (adipose). Antiinflammatory, immune modulatory, facilitate regenerative process after injury. Autologous or allogeneic ( off the shelf ) Mesenchymal Stem Cells or Mesenchymal Stromal Cells (MSC) What are these cells? Mesenchymal cells: from embryology are cells from the mesenchima or mesoderm that will give origin to blood, blood vessels, bone and muscle. Stromal cells: cells from tissue stroma, promotes scaffolding and sustain other cells in the tissue. Mesenchymal Stem cells: cells from the bone marrow that have the capacity to generate bone, fat and cartilage. Mesenchymal Stem Cells Cells with multipotent capacity, emonstrate adherence to plastic istinct immunophenotypic pattern. Bone marrow derived but similar cells are isolated from other tissues. Multipotent mesenchymal stromal cells is another terminology used in the literature and more appropriate for these cells. CTRM: Cellular Product CTRM: Processing/Manipulation 5

6 Cellular Therapy Course Multiple infusions along a period of time or single infusions, or implantation. Engraftment or not (depending on potency) Early toxicities Infusion reactions Late toxicities: Second malignancies (?) Miss-differentiation GVH Malignancy Relapse Milestones are not well defined for all cellular therapies. CTRM: Product Infusion CTRM: Outcomes Cellular Therapy Registry: Current Activity Infusions Registered (n=370) CTRM Received (n=283) Indications Indication N Product Type* Neurologic 282 Cerebral Palsy 173 Auto CBU Congenital Hydrocephalus 58 Auto CBU evelopmental elay 12 Auto CBU Encephalomalacia 10 Auto CBU Hemiparesis 9 Auto CBU HIE 8 Auto CBU Brain Injury 7 Auto CBU Partial agenesis of corpus collosum 2 Auto CBU Other 3 Auto CBU Musculoskeletal 1 Avascular Necrosis of Femoral Head 1 Auto marrow Cellular Therapy Registry: Centers N=6 US centers Transplant centers already reporting to the CIBMTR 6

7 HCT related Cellular Therapy: onor Cellular infusions (CI) Cellular Therapy Related to Hematopoietic Stem Cell Transplantation CI is a common terminology used in the CIBMTR forms. Related to any cell infusion occurring after a HCT without a preparative regimen The donor most times is the same, but it does not need to be. Off the shelf MSCs: health donor pool. Patients may receive GVH prophylaxis. onor Cellular Infusion R LI R R L HCT-related cellular therapy: CI This data is already being collected. TE level- Post-TE Comprehensive Report Forms (CRF) Follow up form (Combine 2100) HCT vs CI Conditioning regimen What was the previous transplant Indication Type of cells infused Changing Chimerism Complete Chimera Indications for CI Lymphocyte Infusions post HCT Relapse prophylaxis Treatment of relapse: CML, AML, MM and others. eclining donor chimerism (graft failure) Treatment of post transplant malignancy: PTL (Lymphoma) Treatment of Viral Infections Treatment of GVH (Mesenchymal Stromal Cells) 7

8 Cytotoxic T-Cells (CTLs) for viral illness Ummanipulated lymphocytes: ecrease numbers of viral specific CTLs Presence of alloreactive T-cell that increase the risk of GVH and further immunessupression. Strategies: ecrease the content of alloreactive T cells; evelopment of virus specific CTLs EBV, Adenovirus and CMV. CI in the Post-TE CI in Form 2100: Follow up forms Cellular Therapy Registration: Moving Forward CI source Cell collection Cell type and doses Product manipulation Challenges Programs on cellular therapy are not the same as HCT, even though same institution. Beyond hematology and oncology fields. Other specialist might not be interested in collaboration. Remains investigational Clinical trials with confidential data. Off the shelf products with similar scrutiny as pharmaceutical products. Cell types being patented. Lessons Learned Participation is limited to transplant centers already contributing to CIBMTR. CTRM outcomes are incomplete There are some gaps in data collection: Collection for cellular therapy for treatment of malignancies Co-infusion of different cell products peritransplant. 8

9 Chimeric Antigen Receptor (CAR)- Transduced T cells Targeting C19 Monoclonal Antibody TcR-complex Tumor Ag Clinical Response in the Patient. Tumor Linker HRS3-scFv v H v L CAR Spacer T Cell Intracytoplasmic Michel Sadelain Porter L et al. N Engl J Med 2011;365: Upcoming Initiatives Update data collection to accommodate changes in the field Collection of infusion of CAR cellular therapy Report on current activity Collaboration with PACT Continue outreach to disease specific groups Autoimmune diseases For more information: mpasquini@mcw.edu Conclusions Cellular Therapy Registry is actively collecting data. CIBMTR transplant centers are the main collaborators. Importance to continue to reach out to disease specialist and explore new collaborations. Continue ongoing revisions to optimize data collection to adapt to a rapidly changing field. 9