Abstract #163 Michael Kalos, PhD

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1 LONG TERM FUNCTIONAL PERSISTENCE, B CELL APLASIA AND ANTI LEUKEMIA EFFICACY IN REFRACTORY B CELL MALIGNANCIES FOLLOWING T CELL IMMUNOTHERAPY USING CAR REDIRECTED REDIRECTED T CELLS TARGETING CD19 Abstract #163 Michael Kalos, PhD 2013 ASH, NEW ORLEANS, LA

2 Adoptive T cell Therapy of Cancer The essential elements of successful adoptive T cell therapy Large number of potent antigen specific T cells Expansion in vivo in response to antigen encounter Potent anti tumor activity Contraction and long term persistence Ability to respond to challenge

3 Autologous T Cells Transduced w/ Anti CD19 mab spliced with TCR ζ and 4 1BB Signaling Domains (CART19=CTL019) Clinicaltrials.gov: NCT UPCC04409 (CLL, ALL) (Porter, Frey) UPCC03712 (CLL, dose finding ) (Frey) CHOP959 (pall pall) (Grupp) MHC independent target recognition Every surface molecule is a target epitope Targeted antibody delivery coupled to potent effector cell activation Lentiviral vector to CD3 ζ ζ and 4 1BB Anti CD3/anti CD28 deliver construct signaling domains mab coated bead stimulation Infuse early post conditioning No cytokine support

4 Summary on previously 2 reported patient cohort CLL (UPCC04409) (Porter et al., NEJM 2011, Kalos et al. SciTM 2011) Both patients in ongoing clinical CR at 3+ years post CTL019 infusion CTL019 cells still detected molecularly (low levels) Both patients in deep complete molecular remissions Ongoing B cell aplasia pediatric ALL (CHP959) (Grupp, Kalos et al., NEJM, 2012) First patient in ongoing clinical CR at 18 months post CTL019 infusion CTL019 cells still detected at 18 months (low levels) Patient in deep and complete molecular remission Ongoing B cell aplasia

5 To date response summary CTL019 studies STUDY DISEASE TOTAL CR PR NR ONGOING CR UPCC CLL 14 4 (29%) 4 (29%) 6 (43%) 4 (10 M+) (29%) UPCC CLL 18 3 (17%) 4 (22%) 11 (61%) 3 (2M+) (17%) CHP 959 ALL (ped) (86%) 0 3 (14%) 14 (3M+) (64%) UPCC ALL (adult) 5 5 (100%) *(4 M+) (80%) In all cases, no further therapeutic treatment intervention post CTL019 infusion (*)

6 Long term CTL019 persistence and ongoing B cell Long aplasia in CR patients

7 Higher levels of peripheral CTL019 cells detected in complete responders Q PCR analysis CTL019 cells/microgram genomic DNA

8 CTL019 T Cells traffic to CNS in ALL copies / μggdna CHP 100 CHP Q PCR analysis: CTL019 cells/microgram genomic DNA BLOOD CSF Blood CSF CHOP-100 CHOP % marking copies / μggdna Blood Day 10 Wright Giesma stain Morphology of CTL019 In Vivo Daysafter Infusion Daysafter Infusion CSF Flow analysis CSF CHOP 100 Day 175 Day 23 FMO CAR CHOP 101 Day 23 CD3

9 Complete responses are associated with deep molecular remissions: IGH deep seqencing IgH deep sequencing (At least 150,000 cell equivalents) CLL patients Patient Tissue timepoint tumor clone frequency Blood Marrow 28 0 Marrow Blood Marrow 31 0 Marrow Blood Blood Blood Blood Blood Marrow Marrow Blood Marrow pall patients Patient Tissue timepoint tumor clone frequency CHP Blood Blood Marrow Marrow Marrow CHP Marrow Marrow 90 0 CHP Marrow Marrow 90 0 Marrow Marrow aall patients Patient Tissue timepoint tumor clone frequency Marrow D Marrow D Marrow D 1 6 Marrow 90 0 Absence of essentially all IgH reads: No B cells present Adaptive Biotechnologies

10 CTL019 Toxicities Cytokine release syndrome (CRS) Macrophage activation syndrome (HLH / MAS Effectively managed by treatment with IL 6 receptor blocking antibody (Tocilizumab) B cell aplasia Observed in all responding patients to date Managed with replacement therapy Tumor lysis syndrome (TLS) May be delayed for 20 to 50 days post infusion

11 Conclusions Engineered T cells may be the first example of successful synthetic biology T cells can be engineered to express antibody fragments that persist and express antibody for at least three years in patients with leukemia Complete and durable clinical responses are associated with robust expansion and long term persistence of CTL019 cells, and in patients with heavy tumor burden delayed Tumor Lysis Syndrome and Cytokine Release Syndrome Infused CTL019 cells are serial killers. Each infused CTL019 cell or its progeny kills on average >1000 leukemia cells CTL019 cells are poised to replace bone marrow transplantation with a therapy p p p py that is less expensive, more widely available and less toxic than current allogeneic stem cell transplantation therapy

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