CD30.CAR-T Treatment of Patients with Relapsed Or Refractory CD30+

Home , CD30, Stanford V

CD30.CAR-T

Treatment of Patients with Relapsed or Refractory CD30+ Classical Hodgkin Lymphoma

Pediatric Subcommittee of the Oncologic Drugs Advisory Committee June 18, 2020 Introduction

 Clinical stage global biotechnology company pioneering development of cell therapies for cancer

 Focused on CAR-T and VST platforms

 Development of transformative therapy for pediatric and adult patients with cancer

 RMAT designation for autologous CD30.CAR-T for R/R cHL

 GMP manufacturing facility to be completed by 2020

2 Agenda

 Rationale for Development of CD30.CAR-T for Classical Hodgkin Lymphoma (cHL)

 Clinical Experience in Adult and Pediatric Patients with Relapsed or Refractory CD30-positive cHL

 Pivotal Trial Design

 Potential Challenges for Clinical Development of CD30.CAR-T for Pediatric Patients

3 Rationale for Development of CD30.CAR-T for Hodgkin Lymphoma

4 Unmet Need in cHL Treatment

OS@ 3yrs: 97.2% ABVD (2 cycles) PFS @ 3yrs: 85.7% OS@2 yrs: 96.6% Brentuximab vedotin + PFS@2 yrs: 82.1% AVD ORR: 86% (CR: 73%) 1L OS@5 yrs: 88% Stanford V (12 wks) mPFS@ 5yrs: 71% ORR: 76.2% (CR: 68.7%) OS @5 yrs: 95.3% . Some patients eventually Dose Escalated PFS@5 yrs: 90.3% BEACOPP (6 cycles) progress and will require ORR: 95.5% (CR: 94.2%) salvage therapy

ORR 75%; mOS: 22.4 mos; mPFS: 5.6 mos Brentuximab vedotin . Integration of Brentuximab OS@5yr: 41%; PFS@5 yr: 22% vedotin and Nivolumab or DHAP (2 cycles) ORR 88% Pembrolizumab to earlier line

ORR 73%; OS@3 yrs: 35% of therapy 2L ESHAP ORR 67%; mPFS 52 mos; OS @ 2 yr 72.6% . No approved therapy post MINE ORR 75%; OS@2 yr: 59% Brentuximab vedotin and/or ORR 84%; OS @ mOS: 87 mos MINI-BEAM Nivolumab/ Pembrolizumab ORR 84%

3L Nivolumab ORR 69%; mPFS: 14.7 mos

4L Pembrolizumab ORR 69% [CR:22.4%] 5 Hodgkin Lymphoma: Low Incidence and Excellent Prognosis for Pediatric Patients

4.5

3.5

2.5

2 Rate (per 100,000) (per Rate 1.5

0.5

a b Incidence Rate Death Rate

Hodgkin Lymphoma in the US: Age-Specific Incidence and Death Rate

a SEER 21 areas. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1130), unless noted. b US Mortality Files, National Center for Health Statistics, Centers for Disease Control and Prevention. Rates are per 100,000 and are age-adjusted to the 2000 US Std Population (19 age groups - Census P25-1130), unless noted. Bars are not shown for rates based on less than 16 cases for the time interval. Source: SEER Cancer Statistics Review 1975-2016, NCI

6 CD30 Expression and Incidence in Pediatric Population of Lymphoma

CD30 is the characteristic marker of classical Hodgkin lymphoma (Gottesman 2016, Weyden 2017)

Lymphoma CD30 Positivity % of total pediatrics Age Publications Subtypes NHL patients ALCL ~100% 10-15% Mean age: 10 years Burkhardt et al., 2005 Lowe et al., 2013 Stein et al., 1985 Suh et al., 2019 PTCL-NOS 64% 1-5% N/A Kontny et al., 2015 Sabattini et al., 2013 Suh et al., 2005 Windsor et al., 2008 ENKTCL ~40-70% Rare N/A El-Mallawany et al., 2012 Kawamoto et al., 2018 Kim et al., 2015 Sabattini et al., 2013 DLBCL 10-31% 8-20% Most common: 15-19 yrs Abramson et. al., 2008 Uncommon in < 5 yrs Burkhardt et al., 2005 Campuzano-Zuluaga et al., 2013 Gong et al., 2018 Hao et al., 2015 Hu et al., 2013 Slack et al., 2014 Salas et al., 2019 Suh et al., 2019 PMBCL 19% 2% N/A Burkhardt et al., 2005 Hoeller et al., 2010

ALCL: Anaplastic large cell lymphoma; DLBCL: Diffuse large B cell lymphoma; ENKTCL: Extranodal N/K T Cell Lymphoma; HL: Hodgkin 7 Lymphoma; PMBCL: Primary Mediastinal Large B Cell Lymphoma; PTCL-NOS: Peripheral T cell lymphoma, not otherwise specified CD30 and Lymphomas

CD30 is expressed in various lymphomas CD30 is a safe antigen to target

CD30 is universally expressed in CD30 is expressed on lymphoma classical Hodgkin lymphoma and cells and is largely absent from expressed to varying degrees in healthy tissues, reducing chance of non-Hodgkin lymphoma subtypes off-tumor cytotoxic effects (e.g. ALCL, PTCL and DLBCL)

CD30 is a validated lymphoma target T cell therapy is an exciting anti-cancer modality

CD30-targeting antibody-drug Very promising CD30.CAR-T cell conjugate brentuximab vedotin clinical data post anti PD1 antibody has been approved for Hodgkin and brentuximab vedotin lymphoma and several non- treatment. Hodgkin lymphomas

CD30 CD30.CAR Tumor cell death Tumor CD30 CD30.CAR CAR-T T cell Recognition and Cells tumor killing

CD30.CAR enables recognition and elimination of CD30+ lymphoma cells

Campuzano-Zuluaga et al., Gong et al., 2018; Gottesman, 2016; Hao et al., 2015; Hoeller et al., 2010; Hu et al., 2013; Kawamoto et al., 8 2018; Kim et al., 2015; Sabattini et al., 2013; 2013; Salas et al., 2020; Slack et al., 2014; Younes and Ansell, 2016 CD30-directed Genetically Modified Autologous T Cells (CD30.CAR-T)

CD30.CAR Construct Manufacturing Process Overview

9 Clinical Experience in Adults and Pediatric Patients

10 Investigator Initiated CD30.CAR-T Trials in Classical Hodgkin Lymphoma

Clinical proof of concept has been demonstrated in three Phase 1/2 clinical trials

Study No. NCT No. Study Description Status & Accrual Sponsor (14 Feb 2020)

LCCC 1544-ATL Study Completed, Phase 1 Study of the Administration of T Lymphocytes NCT01316146 9 patients received Expressing the CD30 Chimeric Antigen Receptor for University of North CD30.CAR-T including 7 HL Relapsed CD30+ HL and CD30+ NHL (CART CD30) Carolina1 patients

LCCC 1532-ATL Study ongoing, Phase 1b/2 Study of the Administration of T Lymphocytes NCT02690545 26 cHL patients treated, including Expressing the CD30 Chimeric Antigen Receptor (CAR) for University of North 1 patient under 18 Relapsed or Refractory CD30+ HL and CD30+ NHL Carolina2

H-37966 (RELY-30) Study ongoing, NCT02917083 Phase 1 Study of Relapsed CD30 Expressing Lymphoma 18 cHL patients treated, including Baylor College of Treated with CD30 CAR T Cells 2 patients under 18 Medicine3

1 NCT01316146; Ramos et al, J Clin Invest, 2017 2 NCT02690545; Grover et al, Blood, 2018; Grover and Savoldo, BMC Cancer, 2019 3 NCT02917083; Ramos et al, Biol Blood Marrow Transpl, 2019; Ramos et al, Blood, 2018

11 Data of cHL Patients from UNC and BCM Clinical Trials

59 underwent cell procurement

15 not treated 44 received infusion • 2 withdrew from trial • 1 manufacturing failure • 1 awaiting treatment at data cutoff date • 5 had sustained responses on bridging 26 patients at UNC 18 patients at BCM therapy • 2 died from progressive disease • 4 not treated due to other reasons 18 HL patients 8 HL patients Benda 18 HL Flu/Cy Flu/Benda 2. lymphodepletion lymphodepletion Benda: Bendamustine 90 mg/m /day lymphodepletion for 2 days Flu/Benda: Fludarabine 30mg/m2/day 3 DL2 1 DL2 3 DL1 and bendamustine 70mg/m2/day for 3 days 2 5 DL3* 17 DL3 6 DL2 Flu/Cy: Fludarabine 30mg/m /day and cyclophosphamide 500 mg/m2/day for 9 DL3# 3 days * 1 received a second infusion (DL3) 7 2 # 2 received a second infusion (DL3) DL1: 2 x 10 cells/m DL2: 1 x 108 cells/m2 DL3: 2 x 108 cells/m2 Note: Data based on 14 February 2020 data cut-off 12 Baseline Patients Characteristics (Population Treated with CD30.CAR-T)

All Patients Benda Flu/Benda Flu/Cy Characteristics n=44* (%) n=8* (%) n=18 (%) n=18* (%) NS 34 (77) 6 (75) 11 (61) 17 (94) HL Subtype: n (%) MC 4 (9) 2 (25) 2 (11) 0 NOS 6 (13) 0 5 (28) 1 (6) I-II 15 (34) 1 (13) 7 (39) 7 (39) Stage at diagnosis: n (%) III-IV 29 (66) 7 (88) 11 (61) 11 (61) Age (years), median (range) 33 (15-69) 49 (23-67) 31.5 (15-45) 33.5 (15-69) Male sex: n (%) 29 (66) 5 (63) 13 (72) 11 (61) Prior Therapies, median (range) 8 (5-17) 7.5 (5-17) 8 (3-23) 5 (2-10) Bridging Therapy: n (%) 28 (64) 8 (100) 10 (56) 10 (56) Prior BV: n (%) 41 (93) 8 (100) 17 (94) 16 (89) Prior CPI: n (%) 34 (77) 7 (88) 13 (72) 14 (78) Prior ASCT: n (%) 34 (77) 7 (88) 14 (78) 13 (72) Prior alloSCT: n (%) 11 (25) 2 (25) 8 (44) 1 (6) 2´107 3 (7) 0 0 3 (17) CAR-T cells/m2: n (%) 1´108 10 (23) 3 (38) 1 (6) 6 (33) 2´108 31 (70) 5 (63) 17 (94) 9 (50)

*One patient who received two treatments (one at UNC and the second at BCM 2 years later) was considered twice

alloSCT: allogeneic stem cell transplant; ASCT: autologous stem cell transplant; Benda: bendamustine; BV: brentuximab vedotin; CPI: checkpoint inhibitor; Cy: cyclophosphamide; Flu: fludarabine; HL: Hodgkin lymphoma; MC: mixed cellularity; NOS: not otherwise specified; NS: nodular sclerosis.

Note: Data based on 14 February 2020 data cut-off 13 CD30.CAR-T Induces Complete Responses in Heavily Pre-Treated cHL Patients

74% ORR with 22 CRs Amongst 34 Evaluable Patients Treated with Fludarabine-based Lymphodepletion

Fludarabine-based Lymphodepletion All Patients Bendamustine* (n =39) (n = 5) Flu/Benda** Flu/Cy Total (n = 16) (n = 18) (n = 34) ORR#: n (%) CR + PR 25 (64%) 0 (0%) 13 (81%) 12 (67%) 25 (74%) CR 22 (56%) 0 (0%) 12 (75%) 10 (56%)*** 22 (65%) PR 3 (8%) 0 (0%) 1 (6%) 2 (11%) 3 (9%) RR: n (%) SD 4 (10%) 1 (20%) 1 (6%) 2 (11%) 3 (9%) PD 10 (26%) 4 (80%) 2 (13%) 4 (22%) 6 (18%)

*Excludes 3 patients **Excludes 2 patients *** 1 PR patient with CRs from with CRs from changed to CR bridging therapy bridging therapy after 2nd infusion

#ORR by investigator assessment, per the Revised Criteria for Response Assessment: The Lugano Classification

Note: Data based on 14 February 2020 data cut-off 14 Significant Efficacy in Heavily Pre-Treated Patients with cHL (I)

Median DoR in 21 patients with CR after Median DoR in 21 patients with CR after 1st infusion = 9.5 months (IQR: 4.4-15.6) 1st infusion = 9.5 months (IQR: 4.4-15.6)

LD CD30.CARTdose n ORR 1 year PFS (95%CI) LD CD30.CARTdose n ORR 1 year PFS (95%CI) Flu/Benda 2 x 10^8 15 12/15 (80%) 57% (28%, 78%) Flu/Benda 2 x 10^8 15 13/15 (87%) 57% (28%, 78%) Flu/Benda 1 x 10^8 1 1/1 (100%) Not estimable Flu/Benda 1 x 10^8 1 1/1 (100%) Not estimable Cy/Flu 2 x 10^8 9 6/9 (67%) Not estimable Cy/Flu 2 x 10^8 9 6/9 (67%) Not estimable Cy/Flu 1 x 10^8 6 4/6 (67%) 17% (0%, 52%) Cy/Flu 1 x 10^8 6 4/6 (67%) 17% (0%, 52%) Cy/Flu 2 x 10^7 3 2/3 (67%) 33% (0%, 77%) Cy/Flu 2 x 10^7 3 2/3 (67%) 33% (0%, 77%)

* *Excluding Excluding 5 5 patients patients having having CR CR from from bridging bridging therapy therapy

Note: Data based on 14 February 2020 data cut-off 15 Bendamustine and Fludarabine Improved PFS

Fludarabine-based lymphodepletion Bendamustine and fludarabine (n=16) compared chemotherapy (n=34) to cyclophosphamide and fludarabine (n=18)

1-year PFS: 1-year PFS: Flu/Benda: 57% (95% CI: 28%-78%) 38% (95% CI: 20% - 55%) Cy/Flu: 21% (95% CI: 5%- 43%)

Results based on 34 evaluable classical HL patients from LCCC 1532-ATL and H-37966 (RELY-30) studies, excluding 5 patients having CR from bridging therapy

Note: Data based on 14 February 2020 data cut-off 16 CD30.CAR-T Therapy Shows Favorable Safety Profile

All patients Benda Flu/Benda Flu/Cy Adverse Events by Preferred Term: n (%) (n= 44) (n = 8) (n = 18) (n= 18) Adverse Events ≥Grade 3 Lymphopenia 37 (84) 8 (100) 18 (100) 16 (89) Leukopenia 21 (48) 3 (38) 8 (44) 11 (61) Neutropenia 17 (39) 2 (25) 7 (39) 9 (50) Thrombocytopenia 10 (23) 1 (13) 7 (39) 3 (17) Anemia 5 (11) 0 3 (17) 3 (17) Hypoalbuminemia 3 (7) 0 0 3 (17) Hyponatremia 2 (5) 0 0 2 (11) Dyspnea 1 (2) 0 0 1 (6) Headache 1 (2) 0 0 1 (6) Pharyngitis 1 (2) 0 1 (6) 0 Lung Infection 1 (2) 0 1 (6) 0 Grade 3/4 Neutropenia at day 28 3 (7) 0 2 (11) 1 (6) Grade 3/4 Thrombocytopenia at day 28 9 (20) 0 6 (33) 3 (17) Grade 3/4 Anemia at day 28 2 (5) 0 0 2 (11) Prolonged Grade 3/4 Neutropenia (at month 3) 0 0 0 0 Prolonged Grade 3/4 Thrombocytopenia (at month 3) 5 (11) 0 3 (17) 2 (11) Prolonged Grade 3/4 Anemia (at month 3) 2 (5) 0 1 (6) 1 (6) Adverse Events of Special Interest Cytokine Release Syndrome (all Grade 1) 10 (23) 1 (13) 2 (11) 7 (39) Rash (Any Grade) 18 (41) 2 (25) 4 (22) 12 (67)

Treatment was well-tolerated with no dose-limiting toxicities • 10 patients (24%) developed cytokine release syndrome (CRS); all were Grade 1 and resolved spontaneously • 18 patients (41%) developed skin rash (1 Grade 3); all resolved spontaneously • Most Grade 3+ toxicities were hematologic and consistent with toxicities caused by LD chemotherapy • Prolonged thrombocytopenia and anemia at month 3 were observed

Note: Data based on 14 February 2020 data cut-off 17 Pediatric Patients with Classical Hodgkin Lymphoma - Safety and Efficacy

No. of Prior Prior Prior LD CD30. Lymphodepletion CAR-T cell Age Sex Prior Response Allo SCT Auto SCT BV Regimen CAR-T Dose Related AE Related AE Therapies

Anemia (G1) Anorexia (G1) ALT Elevated (G1) Cough (G1) Hyponatremia (G1) Flu/ ALT Elevated 15 Female 4 No No Yes 1x108/m2 CR Hypophosphatemia (G1) Benda (G1) Lymphopenia (G4) Neutropenia (G2) Thrombocytopenia (G1) Vomiting (G1) Leukopenia (G2)

Lymphopenia (G4) Leukopenia (G2) 17 Male 6 No No Yes Cy/Flu 2x107/m2 PD None Nausea (G2) Vomiting (G1)

15 Male 7 Yes Yes Yes Cy/Flu 2x108/m2 CR None None

AE: adverse events; alloSCT: allogeneic stem cell transplant; autoSCT: autologous stem cell transplant; ALT: alanine aminotransferase; Benda: bendamustine; BV: brentuximab vedotin; CR: complete response; Cy: cyclophosphamide; Flu: fludarabine; LD: lymphodepletion; PD: progressive disease

Note: Data based on 14 February 2020 data cut-off 18 CD30.CAR-T Expansion and Persistence Enhanced by Fludarabine-based Lymphodepletion Chemotherapy 2E+07/m2 - Cy/Flu (n=3) (n=3) 1E+08/m2 - Cy/Flu (n=6) 1E+08/m2 - Benda 10 5 2E+08/m2 - Benda (n=5) 10 5 2E+08/m2 - Cy/Flu (n=9) 2E+08/m2 - Benda/Flu (n=17) 4 DNA 10 DNA 10 4 ug ug 10 3 10 3

Copies/ 2 10 10 Copies/

1 10 1 10

10 0 10 0 0 7 14 21 28 35 42 49 56 120 180 0 7 14 21 28 35 42 49 56 120 180 Days post CAR-T cell infusion Days post CAR-T cell infusion Note: Data based on 14 February 2020 data cut-off

CD30.CAR-T Expansion and Persistence with or without Cy/Flu Lymphodepleting Chemotherapy

100,000 No Chemo Chemo DL (N=23) – – – – ——— 10,000 DL3 2 x 108 cells/m2 (n=5) (n=5) – – – – ——— DL2 1 x 108 cells/m2 1,000 (n=2) (n=6) gPBMC DNA

μ – – – – ——— DL1 2 x 107 cells/m2 100 (n=2) (n=3)

Vector copies/ Vector 1 0 7 14 21 28 35 42 49 56 Days post CART infusion Note: Data based on June 2019 data cut-off (Ramos et al. 2019 15-ICML, June 2019) 19 CD30.CAR-T Expansion and Persistence in 3 Pediatric Patients Treated in UNC and BCM Clinical Trials

CD30.CAR-T Age LD Regimen Response Dose 17 2x107/m2 Cy/Flu PD

1000000 15 2x108/m2 Cy/Flu CR

100000 15 1x108/m2 Flu/Benda CR 10000 1000 g DNA of µ 100 10

Copies/ 1 0.1 0 2 4 6 8 10 12 14 16 18 20 22 24 Weeks post CAR-T cell infusion

20 Pivotal Trial Design

21 NCT04268706 Pivotal Trial Design in R/R cHL (CHARIOT)

• 82 adult patients will be enrolled globally to yield 66 evaluable adults • 5 pediatric patients (≥12 years of age) will be enrolled and analyzed separately

STUDY TREATMENT STUDY POPULATION Lymphodepletion (3 days) Patients with relapsed or 2 • Flu 30mg/m /day POST- refractory cHL 2 LONG-TERM • Benda 70 mg/m /day TREATMENT • ≥ 12 – 75yo FOLLOW UP FOLLOW UP • Failed 3 lines of therapy: CD30.CAR-T − Chemotherapy Target 2 x 108 cells/m2 Safety and Efficacy Every 6 months − Brentuximab≥ vedotin, and/or Patients< 50 kg: 2.0 to 5.0 x 106 assessments every through M60 and − PD-1 Inhibitor cells/kg body weight 3 months through annually for up to May/may not have received an M24 15 years autologous or allogeneic stem 2nd infusion allowed in patients cell transplant who have CR, PR or SD, then PD at least 3 months after the 1st infusion

Primary Endpoint: ORR with at least 9 months follow up as assessed by an Independent Radiology Review Committee Secondary Endpoints: Safety, ORR as assessed by Investigator, DOR, PFS, OS; HRQoL Exploratory Endpoint: Expansion and persistence of CD30.CAR-T cells in blood; immunogenicity; cytokine profiling; immunological parameters; tumor market and ctDNA Safety Assessments: AE and concomitant medication collection Long-term Follow-up: Additional safety monitoring x 15 years

22 Pivotal Trial Design - Sample Size Considerations

 Primary efficacy endpoint – ORR by Independent Review Committee Assessment  Target – lower bound of 95% Confidence Interval of ORR > 30%  Assumptions – Underlying ORR of 50%, Statistical Power of 90%  Sample Size: . 66 CD30.CAR-T treated adult patients with baseline radiological assessment will be evaluable for primary efficacy analysis . 82 eligible adult patients will be enrolled to ensure the required number of treated patients, assuming 20% patients who may do not receive CD30.CAR-T infusion . A minimum of approximately 5 pediatric patients will be enrolled and analyzed separately

23 Pivotal Trial - Study Procedures

Pre-Treatment Treatment Post-Treatment Follow Up LTFU

Venesection/ Leukapheresis Safety# & Survival Evaluation Period

ICF & Efficacy Evaluation Period Screening Period CD30.CAR-T (~28 days window) Manufacturing

D42 M24 (EOT) M3 M6 M9 M12 M15 M18 M21 (EOS) 15 YR

CD30.CAR-T D0 Infusion

-5 -4 -3 -2 -1

Washout** Baseline Bridging Reassessment Therapy (72 hours prior to LD*)

* Reimaging scan can be done within 1 week prior to LD ** The washout period will be based on the type of agents used as bridging therapy # LD and CD30.CAR-T-association safety evaluation to be performed from Treatment Phase until LTFU Phase.

LTFU: Long Term Follow Up, ICF: Informed Consent Form, LD: Lymphodepleting Chemotherapy, EOT: End of Treatment, EOS: End of Study, M: Month, Y: Year. 24 Bendamustine and Fludarabine Treatment in Pediatric Patients

• Bendamustine is well tolerated by pediatric patients

• Limited experience in HL, ALL, AML with safety profile consistent with adult patients

• Treatment of relapsed/refractory HL pediatric patients with bendamustine 120mg/m2 for 2 days (every 28 days cycle) was well tolerated

• Systemic exposure of bendamustine dosed at 120mg/m2 in pediatrics (1-19 years) was similar to adults

• Fludarabine has been widely used in pediatric patients for a number of malignancies with a tolerable safety profile

25 Pivotal Trial - Pediatric Patients Monitoring

• Patients will be admitted for CD30.CAR-T administration

• Patients will be monitored for 24 hours before being discharged

• Patients will return to the treating facility daily for 10 days (excluding weekends)

• Patients may remain hospitalized post-CD30.CAR-T infusion to monitor for toxicities, per local institutional guidance

• After day 10 or discharge from the treating facility, patients will stay within a 30- minute driving distance to the treating hospital for weekly safety evaluations through month 1

26 Pediatric Patients - Special Considerations for CRS and ICANS

CRS

• Sinus tachycardia as an early sign of CRS is recommended • Age specific definition of hypotension. For hypotension refractory to fluid boluses or hypoxia, consider anti- IL-6 therapy with IV Tocilizumab • Acute respiratory distress syndrome diagnosis and management should be performed per Pediatric Acute Lung Injury Consensus Conference (PALICC) criteria • Acute kidney injury (AKI) in children may be graded by CTCAE v5.0 criteria using the Pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) and Kidney Disease: Improving Global Outcomes (KDIGO) definitions of oliguria and Anuria. AKI was strongly associated with Grades 3 and 4 CRS and developed at a median of 5 days after the start of CRS in pediatric ALL

ICANS/CRES

• Grading of CRES according to CTCAE v5.0 for adult patients is not optimal among infants and younger children. • It is recommended that delirium screening using the CAPD tool or the CARTOX-10 grading system be performed at least twice per 24-hour period among admitted patients and at least daily among outpatients during the high-risk periods for CRES.

Mahadeo et al, Nature Reviews, 2018, Myers et al, 2019 27 Potential Challenges for Clinical Development of CD30.CAR-T for Pediatric Patients

28 Leukapheresis and Manufacturing

Vein to Vein Timeline for US Patients: 7 Weeks

Transduction of T cells with CD30.CAR

PBMCs isolated Ex vivo expansion from blood and of T cells activation of T cells Leukapheresis Infusion

Volume of Blood Required Considerations for Pediatrics . Blood volume allowable for withdrawal from During Leukapheresis pediatric patients >12 (average body weight 40 kg): 32 to 150 mL . . Blood collection in CHARIOT study: Citrate Toxicity. Calculate TBV, SEV, WB flow rate, citrate, calcium ± magnesium infusion • Leukapheresis for T cell production: 30mL rate, heparin infusion if appropriate. • Other tests on the day of leukapheresis . Central Venous Catheter (frequently (infectious disease testing and HLA typing): requires sedation) 45mL . Packed red blood cells (irradiated) and/or  Volume of blood required for leukapheresis albumin can be used to prime the and for other tests is reasonable for pediatric collection in children weighing <30 kg. patients

Lurie Children's Hospital of Chicago IRB Guidelines, 2017; Mahadeo et al, Nature Reviews, 2018 29 CD30.CAR-T Quality Development

30 CD30.CAR-T Quality Development: From Academic Process to Commercialization

1 Enhance controls by applying automation to demonstrate manufacturing consistency and ensure continued product quality control

2 Establish robust product quality control methods and product characterization Academic Commercial

Process 3 Process Qualify a GMP manufacturing facility that is suitable for pivotal trial and commercialization.

4 Establish two-tier cell banking system that will allow for sustainable supply of CD30.CAR vector

Phase 1 / 2 Tessa’s validated process used at commercial process Baylor and UNC

31 Summary

• In spite of great success, there is need for novel therapies in cHL

• CD30 is well validated target for cHL and subset of NHL

• Very encouraging clinical data from two parallel Phase 1/2 trials in R/R cHL

• CD30.CAR-T cell therapy was well tolerated

• CD30.CAR-T received RMAT designation

• Pivotal trial was endorsed by FDA