Presentation is loading. Please wait.

Presentation is loading. Please wait.

CARs and armored CARs Lymphoma and Myeloma 2014 New York NY

Published byRoy Henderson Modified over 9 years ago

Similar presentations

Presentation on theme: "CARs and armored CARs Lymphoma and Myeloma 2014 New York NY"— Presentation transcript:

1 CARs and armored CARs Lymphoma and Myeloma 2014 New York NY
October 23, 2014 Renier Brentjens MD PhD Associate Member Leukemia Service Chief, Cellular Therapeutics Center Department of Medicine Memorial Sloan Kettering Cancer Center 1

2 Conflict of Interest Disclosure
Renier Brentjens MD PhD Stockholder: Juno Therapeutics (scientific co-founder) Royalties: Juno Therapeutics Honoraria: none Reserch Funding: Juno Therapeutics Consultant fees: Juno Therapeutics Discussion of off-label drug use: Tocilizumab

3 Generation of a tumor targeted chimeric antigen receptor (CAR)
α-TAA mAb TCR complex α-TAA scFv—CD8-ζ VH VL 5’ LTR α-tumor scFv CD8 ζ chain 3’ LTR ψ SD SA CAR retroviral vector 3 3 3 3

4 Generation of TAA-targeted T cells for treatment of Cancer
TAA CAR Native TCR αTAA scFv CD8 1. Construct a chimeric antigen receptor (CAR) CD3 ζ 3. Transduce and expand patient T cells ex vivo 4. Infuse transduced T cells to eradicate TAA+ tumor cells TAA CAR 2. Subclone CAR gene into a retroviral vector (SFG) VH VL 5’ LTR αTAA scFv CD8 ζ chain 3’ LTR ψ SD SA TAA SFG-CAR 4 4 4 4

5 Advantages of CAR T cell therapy
HLA-independent antigen recognition, therefore universal application Active in both CD4+ and CD8+ T cells Target antigens include proteins, carbohydrates and glycolipids Rapid generation of tumor specific T cells Minimal risk of autoimmunity or GvHD A living drug, single infusion 5 5 5

6 Expression of CD19 and other B cell markers on B lineage cells
B cell lymphomas and leukemias myelomas preB-ALL Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Stem Cell pro B pre B immature B mature B plasma cell CD19 CD22 CD20 6 6 6 6

7 Evolution in CAR design
7 7

8 Clinical trials using CD19 targeted T cells in relapsed or refractory B-ALL
8 8

9 Patient characteristics and treatment outcomes
Sci Transl Med Mar 20;5(177):177ra38 9

10

11 UPenn studies of relapsed B-ALL
25 pediatric and 5 adult relapsed or refractory B-ALL patients treated 19-4-1BBz CAR design 90% CR 6 month EFS 67% 6 month OSR 78% Maude et al N Engl J Med. 2014, 371:

12 NCI studies of relapsed B-ALL
20 pediatric and young adult relapsed or refractory B-ALL patients treated. 19-28z CAR design 70% CR (14/20) 60% MRD- CR 5 month EFS 78% in MRD- patients Lee et al Lancet. Published online October 13, 2014

13 The Problem

14 Clinical trials using CD19 targeted T cells in low grade B cell malignancies
14 14

15 UPenn clinical trial results
Patient Prior Chemotherapy Conditioning Chemotherapy Response 1 Fludarabine, Rituximab, Alemtuzumab, R-CVP, Lenolidomide, PCR Bendamustine CR (3+ years) 2 Alemtuzumab Bendamustine/Rituximab PR (7 months) 3 Rituximab/Fludarabine, Rituximab/Bendamustine. Alemtuzumab Pentostatin/ Cyclophosphamide Kalos et al Sci Trans Med 2011 15 15

16 Updated UPenn Trials in CLL (ASH 2013)
Abstract 4162 CD19 CAR T cells treating relapsed/refractory CLL Utilizing a 4-1BBz CAR construct, 14 CLL patients treated 3/14 patients obtained CR (21%), 5/14 patients obtained PR (36%), 6/14 patients with no response (43%) 6/14 patients with persistent detectable CAR T cells (5-35 months) No CR patients with reported relapsed disease No dose response reported Abstract 873 Dose randomized dose optimization trial of CLL patients with either high or low dose CAR T cell infusions Utilizing a 4-1BBz CAR construct, 27 CLL patients treated Patients randomized to either low dose (5 x 107 CAR T cells) or high dose (5 x 108 CAR T cells) No dose response benefit seen in these treated patients Overall response rate (CR + PR) was 40% No correlation with CRS and RR was observed 16 16

17 MSKCC clinical trial results: CLL
No Cyclophosphamide Cyclophosphamide Brentjens et al Blood Nov 3;118(18):

18 CAR questions What is the etiology of differential responses by CAR T cell therapy to relapsed B-ALL versus CLL? What is the role of bulky disease and CAR T cell anti-tumor efficacy? The role of the hostile tumor micro-environment and CAR T cell function How to build a better T cell?

19 The hostile tumor microenvironment
The tumor microenvironment contains multiple inhibitory factors designed to potentially suppress effector T cells. CD4+ CD25hi FoxP3+ regulatory T cells (Tregs) MDSCs TAMs Expression of inhibitory ligands by tumor (PD-L1) Tumor secretion of T cell suppressive cytokines (TGF-β and IL-10) 19 19

20 The solution? Armored CAR T cells

21 Moving Forward: Armored CARs
21

22 IL-12 A heterodimeric cytokine secreted by activated APCs, neutrophils and macrophages. Induces Th1 CD4+ T cell response enhancing IL-2 and IFN-γ secretion Enhances T cell clonal expansion and effector function in concert with TCR signaling (signal 1) and CD28 co-stimulation (signal 2), serving as a signal 3. Avoids/reverses T cell anergy May overcome Treg mediated effector T cell inhibition Recruits and activates NK cells Clinical trials in cancer using systemic IL-12 therapy has been limited by severe inflammatory side effects 22 22

23 Syngeneic EL4(hCD19) tumor model
53% IV injection Assess T cell eradication of tumor mCD19-/- hCD19+/- IV injection Assess T cell homing to tumor Assess T cell proliferation in vivo Assess long- term survival of T cells Harvest splenocytes Assess the efficacy of suicide vectors Assess memory T cell response to rechallenge with tumor mCD19-/- hCD19+/- Retroviral transduction with chimeric receptor Determine the side effects of therapy 23 23 23

24 Lymphodepletion enhances anti-tumor efficacy of 19z1+ T cells
2.07% hCD19 Percent Survival hCD19 24.3% Days since tumor cell injection 24 24

25 19z1IRESIL-12 modified T cells secrete biologically active IL-12 and exhibit enhanced targeted cytotoxic function and resistance to Tregs A B C 1:1 2.5:1 5:1 10:1 * D Pegram et al Blood 2012 25 25

26 Syngeneic IL-12 secreting CD19 targeted T cells induce B cell aplasias and tumor eradication
Pegram et al Blood 2012 26 26

27 IL-12 secreting CAR T cells in vivo efficacy

28 IL-12 genetically modified T cells: Armored CAR T cells
NK cell Recruitment and activation NK cell Targeted tumor cytotoxicity IL-12 secretion Targeted tumor cytotoxicity CAR-IRES IL-12 IL-12 secretion Tumor cell Enhanced CM phenotype, enhanced cytotoxicity, enhanced persistence Resistance to Treg and TGFβ inhibition IL-12 secretion Targeted tumor cytotoxicity Reversal of anergy Activated TIL Anergic TIL 28 28 28 28

29 Conclusions Autologous CD19 targeted CAR modified T cells have demonstrated very promising anti-tumor efficacy in B cell ALL with more modest responses in patients with low grade B cell malignancies. Etiologies of CAR T cell resistance may be related to the hostile tumor microenvironment. Application of CAR T cell therapy for low grade B cell malignancies as well as moving forward towards application to solid tumor malignancies requires “armored” CAR T cells designed to both overcome the hostile tumor microenvironment and exhibit enhanced anti-tumor efficacy and long term persistence. “Armored” CAR T cells appear to have enhanced anti-tumor efficacy based on pre-clinical tumor models. Future studies using “armored” CAR T cell technology will focus on translation of these armored CAR T cells to the clinical setting both in the context hematological as well as solid tumor malignancies. 29

30 (Isabelle Riviere, Director) R&D, Manufacturing Xiuyan Wang
Cell Therapy and Cell Engineering Facility (Isabelle Riviere, Director) R&D, Manufacturing Xiuyan Wang Jolanta Stefanski Malgorzata Olszewska Oriana Borquez-Ojeda Teresa Wasielewska Jinrong Qu QA/QC Shirley Bartido Yongzeng Wang (Mark Przybylowski) James Hosey Domenick Pirraglia (Vanessa Capacio) Clinical Research Yvette Bernal Lymphoma Service Craig Moskowitz Ariela Noy GYN service Samith Sandadi Roisin O’Clearbhail Adult BMT Service Sergio Geralt Craig Sauter Department of Clinical Laboratories Lillian Reich David Wuest Kathy Smith Biostatistics Glenn Heller Renier Brentjens Hollie Pegram Mythili Koneru Sarwish Rafiq Swati Pendharkar Eric Smith James Lee Yan Nikhamin Jae Park Kevin Curran Peter Chang Michel Sadelain Marco Davila Michael Gong Jean Baptiste Latouche Leukemia Service David Scheinberg Martin Tallman Mark Frattini Peter Maslak Mark Heaney Joe Jurcic Nicole Lamanna Dan Douer Funding CA59350 (MS) ; P30 CA (CT); 3RO1CA S1(RJB); Alliance for Cancer Gene Therapy ; Terry Fox Run for Cancer Research; William H. Goodwin and Alice Goodwin, and the Commonwealth Cancer Foundation for Research and the ETC of MSKCC; Damon Runyon Clinical Investigator Award (RJB); William Lawrence & Blanche Hughes Foundation (RJB); CLL-Global Research Foundation (RJB) 30 30 30 30 30

31 Brentjens’ Lab Members

Download ppt "CARs and armored CARs Lymphoma and Myeloma 2014 New York NY"

Similar presentations

Porter DL et al. Proc ASH 2012;Abstract 717.

Porter DL et al. Proc ASH 2012;Abstract 717.
John A. Barrett Ph.D. Ziopharm Oncology, Boston MA 02129

John A. Barrett Ph.D. Ziopharm Oncology, Boston MA 02129
Moskowitz CH et al. Proc ASH 2014;Abstract 290.

Moskowitz CH et al. Proc ASH 2014;Abstract 290.
José Pedro Lopes Exhausted CD3 CD8 TCR TIM3 1B11 LAG3 Generated in chronic antigen- mediated TCR stimulation. Express inhibitory receptors and lack effector.

José Pedro Lopes Exhausted CD3 CD8 TCR TIM3 1B11 LAG3 Generated in chronic antigen- mediated TCR stimulation. Express inhibitory receptors and lack effector.
Manuscript summary Chronic Lymphoid Leukemia (CLL) Background Genetically engineering T cells Patient treatment history Engineered T cell therapy and.

Manuscript summary Chronic Lymphoid Leukemia (CLL) Background Genetically engineering T cells Patient treatment history Engineered T cell therapy and.
Ansell SM et al. N Engl J Med 2015;372(4):311-9.

Ansell SM et al. N Engl J Med 2015;372(4):311-9.
Roberts AW et al. Proc ASH 2014;Abstract 325.

Roberts AW et al. Proc ASH 2014;Abstract 325.
Safe and Effective Re-Induction of Complete Remissions in Adults with Relapsed B-ALL Using 19-28z CAR CD19-Targeted T Cell Therapy Davila ML et al. Proc.

Safe and Effective Re-Induction of Complete Remissions in Adults with Relapsed B-ALL Using 19-28z CAR CD19-Targeted T Cell Therapy Davila ML et al. Proc.
Lesokhin AM et al. Proc ASH 2014;Abstract 291.

Lesokhin AM et al. Proc ASH 2014;Abstract 291.
Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019 Cells) Have Long-Term Persistence and Induce Durable Responses in Relapsed, Refractory.

Chimeric Antigen Receptor Modified T Cells Directed Against CD19 (CTL019 Cells) Have Long-Term Persistence and Induce Durable Responses in Relapsed, Refractory.
Beneficial role of antigen commensalism in mesothelin-targeted T-cell therapy for lung adenocarcinoma No Disclosures Adam J. Bograd 1, Jonathan Villena-Vargas.

Beneficial role of antigen commensalism in mesothelin-targeted T-cell therapy for lung adenocarcinoma No Disclosures Adam J. Bograd 1, Jonathan Villena-Vargas.
Kochenderfer JN et al. Proc ASH 2013;Abstract 168.

Kochenderfer JN et al. Proc ASH 2013;Abstract 168.
Results of a Phase II Trial of Brentuximab Vedotin as First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT Chen RW et al. Proc ASH 2014;Abstract.

Results of a Phase II Trial of Brentuximab Vedotin as First Line Salvage Therapy in Relapsed/Refractory HL Prior to AHCT Chen RW et al. Proc ASH 2014;Abstract.
Allogeneic Stem Cell Transplantation: The Journey

Allogeneic Stem Cell Transplantation: The Journey
Lee DW III et al. Proc ASH 2013;Abstract 68.

Lee DW III et al. Proc ASH 2013;Abstract 68.
Patrick Stiff MD Coleman Professor of Oncology

Patrick Stiff MD Coleman Professor of Oncology
T Cells Engineered with a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Produce Significant in Vivo Proliferation, Complete Responses and Long-Term.

T Cells Engineered with a Chimeric Antigen Receptor (CAR) Targeting CD19 (CTL019) Produce Significant in Vivo Proliferation, Complete Responses and Long-Term.
Phase I Trial of Autologous CD19-Targeted CAR-Modified T Cells as Consolidation After Purine Analog-Based First-Line Therapy in Patients with Previously.

Phase I Trial of Autologous CD19-Targeted CAR-Modified T Cells as Consolidation After Purine Analog-Based First-Line Therapy in Patients with Previously.
NW Symposium in Melanoma May 22, 2010 Adoptive T Cell Therapy Cassian Yee MD Member Program in Immunology Fred Hutchinson Cancer Research Center

NW Symposium in Melanoma May 22, 2010 Adoptive T Cell Therapy Cassian Yee MD Member Program in Immunology Fred Hutchinson Cancer Research Center
Dr. Ziad W Jaradat Cancer Stem Cells. Recently biologically distinct and relatively rare populations of tumor-initiating cells have been identified in.

Dr. Ziad W Jaradat Cancer Stem Cells. Recently biologically distinct and relatively rare populations of tumor-initiating cells have been identified in.

Similar presentations

Ads by Google