Pers

onal

ized

Med

icin

e CAR T Cells Travel to the Clinic: Lessons and Expectations

Carl June, M.D. Professor of Pathology and Lab Medicine University of Pennsylvania

February 11, 2014

Abramson Cancer Center

Abramson Cancer Center

Disclosure Information CAR T Cells Travel to the Clinic

Carl June

• PI – David Porter, MD (CLL trial) PI – Stephan Grupp, MD, PhD (ALL trial) PI – Andrew Haas, MD (Mesothelioma trial) PI – Gregory Beatty, MD PhD (Pancreatic trial) Sponsor - Carl June: • Speaker and members of his laboratory have financial

interest due to IP and licensure to Novartis. • Funding support for trials: ACGT, LLS, NCI,

Lustgarten and Novartis • COI managed in accordance with University of

Pennsylvania policy and oversight.

Lesterhuis et al, Nature Reviews 2011

Abridged history of cancer immunotherapy

2011: Ipiliumumab shows overall survival benefit in melanoma (2011) 2012-2013: PD1 and PD-L1 blockade has benefit in melanoma, NSCLC, renal cell (4 NEJM papers) 2011-2013: CAR-modified T cells show durable remissions in B cell ALL and CLL

Updated history of immunotherapy: December 2013

Approaches to Overcome Tolerance

T Cell Immune Surveillance of Cancer

Tumor

T cell response

Elimination

Immunoediting

Escape

Resistance to immune therapy

Evolutionary Biology

Tumor

T cell response

Elimination

Immunoediting

Engineered T cells Tumor elimination

Synthetic Biology

Redirecting the Specificity of T cells – Proposed Mechanism of Action of CAR T cells

§ Gene transfer technology is used to stably express CARs on T cells, conferring novel antigen specificity1,2

§ CART19 cells can thus be directed against any tumor cell that expresses the CD19 surface antigen

§ CART19 therapy takes advantage of the cytotoxic potential of T cells thereby killing tumor cells in an antigen-dependent manner1,3

§ Persistent CART19 cells consist of both effector (cytotoxic) and central memory T cells3

§ T cells arer non-cross resistant to chemotherpy

§ Responses are cytolytic: no swelling!

1. Milone MC, et al. Mol Ther. 2009;17:1453-1464. 2. Hollyman D, et al. J Immunother. 2009;32:169-180. 3. Kalos M, et al. Sci Transl Med. 2011;3:95ra73.

T cell

CD19

Native TCR

Tumor cell

CTL019 cell

Dead tumor cell

Anti-CD19 CAR construct

Using Synthetic Biology to Overcome Tolerance Creation of Bi-specific T cells

TCR

CD3

z

a b

e e

z

g d

z - ITAM

Extracellular

Intracellular

Chimeric Protein

Tumor binding domain

Signaling domain

TCR heterodimer approach “CAR” or T body approach

- off the shelf - MHC independent

1. Sensitive signal amplification

derived by evolution 2. Low avidity 3. Targets intracellular

proteome 4. Requires MHCI expression

and HLA matching on tumor cell

5. Life long persistence (14 yrs) 6. Toxicity difficult to predict…

Engineered CARs and TCRs: which is “better”?

1. Signal amplification

derived by synthetic biology

2. Avidity controllable 3. Targets only surface

structures 4. MHC independent: “off

the shelf” 5. Decade long persistence

TCR CAR

The First “CAR” Trial: CD4z Chimeric Antigen Receptor for HIV

TCR

CD3

z

CD4z CD4

a b

e e

z

g d

z

- ITAM

Extracellular

Intracellular

Irving, B.A., and A. Weiss. Cell 1991; 64:891-901 Mitsuyasu et al, Blood 2000;96:785-93 Walker RE et al. Blood. 2000;96(2):467-74 Deeks SG et al. Mol Ther. 2002;5 788-97

CD4z Sponsored Clinical Trials

ONR Sponsored Randomized Phase IIa Trial (Aronson, et. al.)

Patients: controlled measurable HIV infection with ARV. Three groups: IL-2 , CD4z T cells or CD4z T cells with IL2.

Single infusion of ~8x109 T lymphocytes

>7yr in follow ups 1.2 million IU/m2/day subcutaneous IL-2 for 56 days

A single infusion of 2-3x1010 CD4 and CD8 cells

0

Cell Genesys Phase I open label (Mitsuyasu, et. al.) Patients: controlled measurable HIV infection with ARV. Two groups, infusions of transduced CD4z with or without IL2.

1 2 3 4

6 million units of IL2 infused continuously for 4 days beginning 4hrs prior to T cell infusion.

>9yr in follow ups

Weeks

0 2 4 Weeks

Cell Genesys Randomized Phase II Trial (Deeks, et. al.)

1010 CD4 and CD8 cells infused 3x 2 weeks apart

Patients: controlled HIV infection with ARV. Two groups, infusion with or without CD4z.

>11yr in follow ups

2D Graph 4

X Data

0 1 2 3 4 5 6 7 8 9 10 11 12

Y D

ata

1e-1

1e+0

1e+1

1e+2

1e+3

1e+4

1e+5

Long Term Follow Up: CD4zeta CARs Safety and Stable Persistence

Mean

Outliers

Range

2nd and 3rd quartiles

CD

4-ze

ta c

opie

s pe

r 1e6

PB

MC

Years Post Infusion Detected Tested

19 19

20 20

32 33

30 31

27 27

26 26

24 24

14 15

8 8

4 4

1 1

LOD

Annual Follow ups Half-life: >17yrs

Scholler et al. Science Translational Medicine 4:132Ra153, 2012

Vaccinia specific IgG+ memory B cells

R2=0.68 Initial half life ~1yr, Plateau at 0.1%

Crotty, et al, J Immunology, 2003, 171:4969

Previous studies of human B and T cell survival after smallpox vaccination

Vaccinia specific T cell memory Linear regression analysis

R2=0.57 CD4 Half life ~14yrs

CD4zeta CARs: persistence and safety Infusions of CD4z modified T cells results in long term (>decade) persistence at stable levels of ~0.5% of T cells. 37 of 39 patients have CD4z persistence in PBMC up to 11 years post infusion. No integration near oncogenes or tumor suppressor genes No SAE in >568 years of patient followup

Scholler et al. Science Translational Medicine 4:132Ra153, 2012

• Retrovirus transduced T cells are not associated with delayed adverse events.

• Retrovirus-modified T cells are capable of long term persistence at >0.1 % PBMC in vivo for at least 10 yr.

• Engrafted cells continue to express transgene transcripts (not shown).

• The mechanisms of persistence are not yet known. ü Conclude: T cells with “stemness” can be

modified and engraft

CD4z CAR Retroviral Studies: Summary

Design of CART19: Choice of 4-1BB Signaling Domain Promotes CAR T Cell Proliferation/Survival

Finney et al. J Immunol 2004 Imai et al. Leukemia 2004 Milone, et al. Mol Ther 2009 Carpenito, et al. PNAS 2009

ntd

100 101 102 103 104

97%

Zeta

(3160)

100 101 102 103 104

76%(2467)

BBz

100 101 102 103 104

81%(981)

28z

100 101 102 103 104

89%

28BBz

(695)

100 101 102 103 104

Δz

94%(2367)

100 101 102 103 104

cell

coun

ts

Unmet Need in Relapsed/Refractory B-cell Malignancies

1. SEER Cancer Statistics Review (www.seer.cancer.gov). 2. Brown JR. ASH Education Book. 2011;1:110-118. 3. Ko R, et al. J Clin Oncol. 2010;28:648-654. 4. Hunger SP, et al. J Clin Oncol. 2012;30:1663-1669. 5. Kantarjian H, et al. Cancer. 2004;101:2788-2801. 6. Kantarjian H, et al. Cancer. 2010;116:5568-5574.

§ There is a need for better therapeutic strategies that specifically target B-cell malignancies and improve patient outcomes

17

CLL § 15,680 new cases will be diagnosed and

4,580 will die of CLL in the US in 20131

§ Overall 5-year survival is 79%1

§ CLL is incurable except by allogeneic stem cell transplant (ASCT)2

• Few candidates are eligible for ASCT

§ Patients with relapsed/refractory disease have poor prognosis2

ALL § 6,070 new cases will be diagnosed and

1,430 will die of ALL in the US in 20131

§ Most common childhood malignancy, but also affects adults (median age 14)1

§ In pediatric patients, overall survival is 80-90%, however, ~20% will relapse3,4

§ Although up to 80% of adults will achieve an initial complete response, majority will relapse5,6

§ ASCT is a curative option for eligible patients

Human CD19 expression by hematopoietic cells within the spleen and lymphoid tissues

Tedder, T. F. (2009) CD19: a promising B cell target for rheumatoid arthritis Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2009.184

1. Leukapheresis: the patient’s own T cells are harvested

2. T cells are activated and genetically transduced ex vivo with a construct encoding the anti-CD19 chimeric antigen receptor

3. CTL019 cells undergo ex vivo expansion on antibody-coated beads

4. Chemotherapy (optional step): patient may receive a preparative lymphodepleting regimen before T-cell infusion

5. CTL019 cells are reinfused into the patient where they undergo in vivo expansion and target CD19+ cells for destruction. They remain persistent in the body to guard against residual or recurring disease

Porter DL, et al. N Engl J Med. 2011;365(8):725-733. Porter DL, et al. J Cancer. 2011;2:331-332.

Kalos M, et al. Sci Transl Med. 2011;3:95ra73.

General approaches for engineered T-Cell therapy

CLL Study Overview- ClinicalTrials.gov #NCT01029366

Leukocyte apheresis

CD3/28+ selection of T cells with

anti-CD3/anti-CD28 mAb- coated

magnetic beads

Seed in gas permeable bags.

Transduce with

αCD19–4-1BBζ vector

Vector wash out. Culture in

gas permeable bags

Culture in WAVE

bioreactor

Remove beads

Harvest, Wash,

concentrate

Cryopreserve product in infusible cryomedia

Day 0 Day 0–1 Day 3 Day 5 Harvest Day (10±2)

CART19: αCD19-41BB-CD3ζ transgene

EF1α promoter

CD8α linker CD19 VL

GGGSx4 linker

CD19 VH CD8α hinge and transmembrane region TCR-ζ signaling domain 41-BB signaling domain

Protocol Status: enrollment completed April 2013

CD

19+

hem

e m

alig

nanc

y

FDA approved therapy

Monitor for recurrence

Relapse

elig

ibili

ty tu

mor

rest

agin

g

Week -4

Apheresis #1

PBMC baseline assays

Production/cryopreservation of CART-19 cells

CART-19 infusion 0.3 × 106 – 1.0 × 108 cells/kg

Lymphocyte depleting

chemotherapya

Week -1 Day 0, 1, 14b

(intrapatient dose escalation)

Week ≈+4 (depending on last infusion)

PBMC endpoint analysis

• Monthly observation for 6 months

• Quarterly observation up to 2 years post infusion

• Follow-up for 15 years as mandated by FDA for gene transfer protocols

Day -21UPN 01

Day 177

R/B R/B B

CARs

Days from Infusion-80 -40 120 160 200

Cel

ls(x

10-3/m

m3 )

0

10

20

30

40

50

60

70

80WBCALC

Corticosteroidsstarted

80400

UPN 03

UPN 02

Pre-Therapy 3 Months

Examples of Clinical Responses

David Porter, MD

Baseline

UPN #18: 10 prior therapies, transformed CLL, del(17p), ibrutinib resistant,

XRT resistant

Month 2 BM and blood NED

Month 3 BM and blood NED

Kinetics of Response in Advanced CLL

David Porter, MD

CART19 CLL: Generalities on First 3 Treated Patients Ø All 3 patients had Chronic Lymphocytic Leukemia (CLL)

ü Late stage incurable leukemia

ü 3.5-7 pounds of tumor/patient

Each infused CAR T cell or its progeny

killed more than 1000 tumor cells: CARs are “Serial Killers”

Remissions durable to date

Sustained antibody delivery with a single infusion

of engineered T cells (beyond 3+ yrs)

Porter, D.L. et al.. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia New England Journal of Medicine 365:725-733.

Kalos, M., et al . 2011. T cells expressing chimeric receptors establish memory and potent antitumor effects in patients with advanced leukemia. Science Translational Medicine 3:95ra73.

Pharmacology and Pharmacokinetics of CTL019

A CART 19: Blood

Day (post infusion)

copi

es/m

ggD

NA

0 20 40 60 80 100 120 140 160 180

1

10

100

1000

10000

100000

UPN 03

UPN 01UPN 02

CART19 cells proliferate 2 to 4 log10 in all patients in vivo

1. CAR moiety expressed for at least 6 months

2. Sustained antibody delivery with a single infusion of engineered T cells!

3. CARs expressed for at least 3 years

10 10 2 10 3 10 4 10 5

10 3

10 4

10 5

CD8Day 56

210

27.2

64.3

Recent publications: pediatric and adult ALL

Brentjens, RJ, et al. CD19-Targeted T Cells Rapidly Induce Molecular Remissions in Adults with Chemotherapy-Refractory Acute Lymphoblastic Leukemia. Sci Transl Med 2013; 5:177ra138. Grupp, SA, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. New England Journal of Medicine 2013; 368: Mar 25.

ü efficacy in advanced pre-B cell ALL - 7 of 7 patients achieved CR!

ü toxicity in adults and children is equivalent

Dismal Outcome for 2nd+ Relapse of ALL

Resimuller et al. JPHO 2013

10 year EFS 30-40% can obtain another remission

Leukemia is still the #1 cause of pediatric cancer mortality: NOVEL THERAPIES ARE NEEDED

Over 50 patients have been treated with CART19 (CLL and ALL) ALL: 22 Children - Refractory or 3rd+ Relapse - 3 to 8+ prior therapies - 13 with prior allo BMT - Median donor chimerism 100% ALL: 6 Adults

• 5 of 6 patients CR. Longest duration +10months

Clinical Update of Pediatric and Adult ALL Patients Treated with CART19

CR

CR, transient

PR

BM CR, 1 skin lesion CR, no CARs 2 mo, relapsed at

8 mo: retreat, CR

CR

NR

CR, MRD neg, relapsed at 3 m

CR, MRD 0.1%, transient

CR CR, developed MDS

CR, MRD 0.1% (T Cell)

CR

NR

CR

CR

CR

CR

CR

CR

CR

CR

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

CHP100

CHP101

CHP103

CHP104

CHP105

CHP108

CHP110

CHP111

CHP112

CHP113

CHP114

CHP107

CHP117

CHP115

CHP118

CHP120

CHP121

CHP123

CHP124

CHP125

CHP126

CHP127

Months

Duration of Response (as of 15 November 2013)

Summary of Efficacy in ALL (n=22) 19 CR (5 not sustained), 3 PR/NR

• CR 19/22 (86%) • PR/NR 3/22 (14%)

0

5

10

15

20

GrossDisease

(>5% blasts)

MinimalDisease(<5%)

MRDnegative

No.

of P

atie

nts

CR, MRD-CR, MRD+/unknownNRRelapse

Disease Burden at Time of Infusion and Response

Patient population • ≥ 2nd relapse • Majority refractory

to multiple prior therapies

Single leukemia cutis lesion, remains in BM MRD- CR

Abbreviations: BM, bone marrow; CR, complete response, MRD, minimal residual disease; NR, no response

CTL

019

D+1 D+15 D+21

CR No CR Persistence of CTL019 cells

145 days* Range 15-512 *many ongoing

28 days Range 11-45

p<.05

Persistence out to >3 years in some patients

Peripheral Expansion of CART19 Cells

Efficient Trafficking of CTL019 T Cells to CNS in ALL Morphology of CARs In Vivo

CSF Day 23

Blood Day 10

1

10

100

1000

10000

100000CSF

Days after Infusion100 120 140 160 1800 20 40 60 80

copi

es/m

ggD

NA

Days after Infusion100 120 140 160 180

copi

es/m

ggD

NA

1

10

100

1000

10000

100000 CHOP-100CHOP-1011% marking

0 20 40 60 80

Blood

Stephan Grupp, NEJM 2013

This provides rationale for use of CARs for

neuro-oncology

Potential Roles of CAR T Cells for ALL

32

• Consolidate patients with MRD • Reinduce remission • Produce MRD (-) state prior to allo SCT • Bridge to SCT • Multicenter trials in pediatric ALL (Novartis)

§ With adequate persistence, can we imagine a replacement for allo-SCT? - cancer “stem” cells can persist >1 decade

Roadblocks to Successful Cellular Immunotherapy for Cancer

PROBLEM

• Targeting

• Expansion ex vivo

• Expansion in the host

• Persistence

• Toxicity

SOLUTION

• For ALL, CD19 CAR

• CD3/CD28 beads

• Up to 10,000x in vivo

• Out to >3 years in CLL

• IL-6 receptor blockade

CART19 Toxicities

• B cell aplasia Ø observed in all responding patients to date Ø managed with replacement therapy

• Tumor lysis syndrome (TLS) Ø may be delayed for 20 to 50 days post infusion

• Cytokine release syndrome (CRS) Ø reversible, on-target toxicity Ø Severity related to tumor burden: Treat MRD as outpatient?

• Macrophage activation syndrome (HLH / MAS) Ø elevated serum ferritin (>500,000 ng/ml), CRP, D-dimer Ø elevated cytokines: IL-6, IFN-gamma Ø Reversed with tocilizumab

Tocilizumab Anti-Cytokine Therapy for Cytokine Release Syndrome

CLL Pt 04409-09

94

95

96

97

98

99

100

101

102

103

104

7.12a

7,6a

7.12p

7.6p

8.12a

8,6a

8.12p

8.6p

9.12a

9,6a

9.12p

9.6p

10.12a

10,6a

10.12p

10,6p

11.12a

11,6a

11.12p

11,6p

12.12a

12,6a

12.12p

12,6p

13.12a

136a

13.12p

13,6p

14.12a

14,6a

14.12p

14,6p

Temp (deg F)

Tocilizumab, d10

David Porter, MD

Pilot Trial Testing CD19 CARs for Chemotherapy-Resistant/Refractory Leukemia: Status

Protocols ongoing: 55 patients infused (35 CLL; 20 ALL)

Clinical Responses: CR+PR 72%

First Patient Dosed: 7/31/2010

55 patients treated to date. How do we plan to treat 1000s?

Outscaling CAR manufacturing: robotic and automated cell culture

CAR: Sedan CAR: CD19

Bead addition

Bead removal

T-cell infusion

Beyond leukemia and lymphoma: engineered T cells for other cancers

• Numerous CARs targeting various surface molecules are being developed for many cancer histologies

• Examples: • EGFRviii for glioblastoma • PSMA for prostate cancer • Mesothelin for ovarian, pancreatic cancer and

mesothelioma • Her2/neu (c-erB2) for breast and other

carcinomas • FAP to target tumor stroma

• Key challenges and solutions this is text

Anti-mesothelin CARs engineered with lentiviral vectors have potent anti-tumor effects in pre clinical models

Carpenito, PNAS 2009

The potential bad news

Zhao et al. Cancer Research, 2010

RNA CARs Toxicity management strategy and more?

CAR Expression

PHASE I CLINICAL TRIAL OF AUTOLOGOUS MESOTHELIN RNA CAR T CELLS ADMINISTERED INTRAVENOUSLY IN PATIENTS WITH PROGRESSIVE MALIGNANT PLEURAL MESOTHELIOMA AND PANCREATIC CANCER: DEMOGRAPHICS

Gregory Beatty, MD PhD and Andrew Haas, MD Maus et al, Cancer Immunol Research, 2013

Subject Age/sex Disease Prior therapies Co-morbidities Sites of disease at enrollment

Total infusions received and route of

administration

17510-105 81/M Malignant pleural mesothelioma

Pemetrexed/carboplatin (10 cycles) Pemetrexed (17 months) Intrapleural adenovirus-IFNa gemcitabine

asthma

Bilateral pleura, mediastinal and peritoneal lymph nodes

2 iv infusions (cohort 1); 1 iv infusion (cohort 2); total of 3 iv infusions

21211-101 75/M Pancreatic adenocarcinoma

Gemcitabine/CDDP (3 cycles) Modified FOLFOX6 (9 cycles)

-DVT on LMWH -Abdominal infections -h/o AML s/p syngeneic BMT 5 yrs prior to enrollment

Abdominal mass, liver masses, peritoneal nodules, ascites, Right knee subcutaneous

8 iv infusions; 2 intratumoral injections; 1 intraperitoneal injection

Estimated 57% decrease in volume

Mesothelioma Patient #3: Partial Response

Pre cohort 1 extension Post cohort 1 extension

0

100

200

300

400

500

Total Cells

Tumor cells

Cel

l Cou

nt/m

L As

cite

sDay 3Day 15

Baseline Day +34 B

C D

Mes

othe

lin

c-met

Isotype Control Ascites

66.6% 13.3% 4.8% 15.3%

1.3% 0.2% 2.0% 96.5%

21211-101

Day +77

Baseline

Day +77 Day +34

01234567

SUV m

ax

10

100

1000

10000

Met

abol

ic A

ctiv

ity

Pancreatic Cancer Patient #1: Antitumor Effects after RNA

meso CAR infusions (transient, not sustained)

Vaccine Effect following RNA CAR Meso T Cell Infusions: cross priming?

Western blot analysis on autologous tumor cell line: induction of anti-tumor antibodies

Pt 17510-105 Pt 21211-101

Day +64

Vaccine Effect following RNA CAR Meso T Cell Infusions: cross priming?

Seromics. Protoarray analysis of serum samples from pancreatic cancer patient 21211-101. Pre- day+44

Database ID Ultimate ORF ID Description Intensity Intensity Ratio post/pre BC003548.1 IOH4864 polymerase (DNA directed), lambda (POLL) 564 62,437 110.70

NM_015129.3 IOH27517 septin 6 (SEPT6), transcript variant II 431 28,447 66.08 NM_003677.3 IOH56971 Density-regulated protein 431 18,521 43.02 NM_145802.1 IOH14040 septin 6 (SEPT6), transcript variant V 431 12,692 29.48 NM_033003.1 IOH5665 general transcription factor II, i (GTF2I), transcript variant 4 654 18,769 28.70 NM_053031.2 IOH59941 Myosin light chain kinase, smooth muscle 430 10,117 23.50

NM_015927.2 IOH3924 transforming growth factor beta 1 induced transcript 1 (TGFB1I1), transcript variant 2 687 15,098 21.98

NM_000431.1 IOH10122 Mevalonate kinase 2,517 49,352 19.61 NM_003315.1 IOH14566 DnaJ (Hsp40) homolog, subfamily C, member 7 (DNAJC7) 430 7,733 17.96 NM_006759.3 IOH26550 UDP-glucose pyrophosphorylase 2 (UGP2), transcript variant 1 697 12,385 17.78 XM_376764.2 IOH40703 paraneoplastic antigen MA2 (PNMA2) 1,759 27,277 15.51 NM_016954.2 IOH46151 T-box 22 (TBX22), transcript variant 2 430 6,653 15.45 BC012899.1 IOH11155 sialidase 4 (NEU4) 636 9,721 15.28 BC036846.1 IOH28739 protease, serine, 33 (PRSS33) 899 13,007 14.48 BC007637.1 IOH6973 chromosome 1 open reading frame 94 (C1orf94) 950 10,953 11.54

NM_024825.2 IOH29237 podocan-like 1, mRNA (cDNA clone MGC:71618 IMAGE:30347370), complete cds 430 4,865 11.30

BC000 2 1 IOH362 glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate

i f 2) (GOT2) 6 105 62 995 10 47

Summary

• CD19 CARs have potent anti-leukemic effects in ALL and CLL with durable responses >3 years. CD19 CARs induce B cell aplasia • Managed with IVIG infusions

• Anti-mesothelin mRNA CARs are safe (24 infusions to date) and anti-tumor effects observed in 2 of 4 evaluable patients: one with mesothelioma and one with pancreatic cancer.

• Evidence for “vaccine” effect with RNA CARs: cross priming?

CAR Trials: Colleagues and Collaborators PENN Medicine

David Porter Noelle Frye Elizabeth Hexner Stephen Schuster Edward Stadtmauer Alison Loren Lynn Schuchter Martin Carroll Gregory Beatty Robert Vonderheide Adam Bagg Don Siegel Sharyn Katz Ran Reshef Sunita Nasta Saar Gill Alison Rager Jacob Svoboda

ACC Translational Research Anne Chew Sonia Guedan Carrio Joseph Fraietta Omkar Kawalekar Jihyun Lee Marcela Maus Michael Milone Roddy O’Connor Gabriela Plesa John Scholler T Cell Engineering Yangbing Zhao Xiaojun Liu Shuguang Jiang

Children’s Hospital of Philadelphia Stephan Grupp David Barrett RNA CAR Mesothelin Gregory Beatty Andrew Haas Marcela Maus Steven Albelda

CVPF Bruce Levine Zoe Zheng Alexey Bersenev Andrea Brennan Julio Cotte Elisabetta Cribioli Jos Melenhorst Chris Nowaczyk Hima Patel Suzanne Pavluk Tamara Tripic

TCSL Michael Kalos Irina Kulikovskaya