CAR T-Cell Therapy: Efficacy, Treatment, Access Michael I. - - PowerPoint PPT Presentation

CAR T-Cell Therapy: Efficacy, Treatment, Access

Michael I. Nishimura, Ph.D.

Professor of Surgery and Vice Chair for Surgery Research Stritch School of Medicine Tumor Immunology & Immunotherapy Program Cardinal Bernardin Cancer Center Loyola University Chicago

Disclosures

• Basic, Translational, Pre-clinical and Clinical

studies supported in total or in part by following NIH grants:

• R01 CA90873 (MN, inactive)
• R01 CA102280 (MN, inactive)
• R01 CA107947 (MN, inactive)
• R01 CA107947 S1, ARRA Supplement (MN, inactive)
• P01 CA154778 (MN, inactive)
• R21 CA153789 (MN, inactive)
• R21 AR056624 (SM, inactive)
• R01 CA138930 (SM, inactive)
• R01 AR054749 (ICL, inactive)
• R01 AR057643 (ICL, inactive)
• R01 AI129563 (BB & MN MPI, active)
• Lentivirus vector development studies supported

by subcontracts from the Lentigen Corp.

• R43 CA126461 (BD, inactive)
• R44 CA126461 (BD, inactive)
• CD19 CAR studies supported by a generous gift

from the Leukemia Research Foundation

• Basic, Translational and Pre-clinical studies

supported in part by the following Department of Defense grant:

• Idea Development Award 110036 - W81XWH-

12-1-0185 (ICL, inactive)

• Pre-clinical studies supported in part by a

grant from the Falk Foundation:

• Catalyst Research Program Award (MN,

inactive)

• Transformtional Research Award (MN, active)
• rhIL-15 and other cytokines for the

preclinical studies and clinical trials generously provided by the Biological Resources Branch, DCTD, NCI

• Conflict of Interest
• Consulted for Sanofi S.A.
• Chair SAB for T-Cure
• SAB for Moderna Therapeutics
• SAB for Anocca, AB

Acknowledgements

• Med. Univ. South Carolina

Shikhar Mehrotra Amir Al Khami Navtej Kaur Pravin Kesarwani Osama Naga Shahid Hussain Keisuke Shirai Elizabeth Garrett-Mayer

Nishimura Lab

Glenda Callender Timothy Clay David Cole Mary Custer Annika Dalheim Matthew DeJong Telma da Palma Erica Fleming-Trujillo Kendra Foley Elizabeth Grindstaff Elizabeth He Wood Barbara Kaplan Aaron Lesher Mingli Li Gretchen Lyons Mark McKee Tamson Moore Kelly Moxley David Murray Hakan Norell Jeffrey Roszkowski Pablo Sanez-Lopez Larrocha Gina Scurti Thomas Smith Timothy Spear Natalie Spivey Mallory Thomas David Yu Siao-Yi Wang

NHLBI, NIH

Richard Childs Adriana Byrnes Elena Cherkasova Rosa Nadal Rios

BRB, NCI, NIH

Jason Yovandich Stephen Creekmore

Loyola University Medical Center

Jose Geuvara Phong Le Clinical Team Joseph Clark Constantine Godellas Nasheed Hossain Kelli Hutchens Ann Lau Clark Karen Pilman Diane Palmer Mala Parthasarathy Courtney Wagner Jodi Seiser Patrick Stiff

• Univ. Colorado Denver

Hugo Rosen Lucy Golden-Mason Rachel Leistikow Rachel H. McMahan

University of Notre Dame

Brian Baker Fernando Huyke Lance Hellman Nishant Singh Yuan Wang

Lentigen Corporation

Boro Dropulic Heather Embree Rimas Orentas

University of Utah

Brian Evavold Elizabeth Motunrayo Kolawole

Northwestern University

• I. Caroline Le Poole

Emilia Dellacecca Jonathan Eby Jared Klarquist Jeffrey Mosenson

Earle Chile Research Institute

Brendan Curti Christopher Fountain Bernard Fox Tarsem Moudgil Walter Urba

Karolinska Institute

Rolf Kiessling Yuneng Mao Eiji Miyahara

Objectives

1) Brief History and Rationale for Adoptive T-Cell Therapy for Cancer

1. Overview of Cancer Immunotherapy 2. Adoptive Cell Transfer Therapy a) Stem Cell Transplantation b) Tumor Infiltrating Lymphocytes (TIL) 3. Lymphodepletion

2) Reasons for Using Genetically Modifying T Cells

1. Altering Antigen Specificity a) Types of receptors used for gene therapy b) Chimeric Antigen Receptors i. Evolution/Generations of CAR ii. Targets for CAR Therapy iii. Why CD19? iv. Clinical Outcomes c) T Cell Receptors i. Targets ii. Clinical Outcomes

3) Gene Modified T Cells – Loyola Experience

1) Manufacture, purification, and tracking of transduced T cells in humans 2) Clinical trial Design 3) TCR gene modified T cell clinical trial results

– The immune system has evolved to enable us to fight various pathogens (virus, bacteria, fungus, etc.) – The immune system must first know what is “normal self” before it can know what should be attacked – Since cancer is derived from normal cells, with few exceptions, the immune system is not very efficient at recognizing and eliminating cancer cells naturally.

Immunotherapy For Cancer

Goal:

To boost the host anti-tumor immune response leading to regression

• f widely disseminated disease and prevention of recurrent disease.

Approaches:

1) Cytokines (IL-2, IFN-g, GM-CSF, and others) 2) Vaccines (Peptide, recombinant protein, whole cell, cell extract, dendritic cell, recombinant virus, and others) 3) Monoclonal antibodies

a) Therapeutic b) Blocking

4) Adoptive cell transfer

1) LAK 2) T cells 3) NK cells 4) Stem cell transplantation (autologous, allogeneic, cord blood)

Immunotherapy For Cancer

Immunotherapy For Cancer

Allogeneic Stem Cell Transplant

Rezvani et al. Bone Marrow Transplant. 2015 From Winthrop P. Rockefeller Cancer Institute Web Site

TIL Therapy

Rosenberg et. al., J Natl Cancer Inst ;85:622-632, 1993

Tumor Infiltrating Lymphocytes: – T cells are chemotactic and can migrate to sources of antigen – Tumor-reactive T cells can accumulate in tumor lesions – TIL cultures can recognize many HLA matched tumors or only the autologous tumor – TIL can be expanded from some tumors to therapeutic numbers

Total number Objective response rate Treatment

• f patients

CR PR CR + PR IL-2 134 9 14 23 (17%) TIL + IL-2 86 5 24 29 (34%) Prior IL-2 28 1 8 9 (32%) No prior IL-2 58 4 16 20 (34%)

Rosenberg et al., JNCI 86:1159-1166, 1994

TIL Therapy

Lymphodepletion/Homeostatic Proliferation

Homeostasis:

1) The hematopoietic system regulates the number of each cell type in the blood, lymphoid organs, and bone marrow. 2) Depletion of one or more of these hematopoietic cell types leads to mobilization of the progenitors to restore the population to normal.

Lymphodepletion:

1) Chemotherapy and/or total body irradiation can destroy the hematopoietic system leading to homeostatic proliferation of the depleted cell types.

Lymphodepletion Prior to T Cell Infusion

Advantages:

1) The cytokines and other factors that drive the hematopoietic system to regenerate also favor the expansion of the adoptively transferred T cells, both normal and gene modified. 2) Suppressor cells derived from the hematopoietic system (Treg, myeloid derived suppressor cells, etc.) are eliminated.

Disadvantages:

1) Chemotherapy and/or total body irradiation leads to immune suppression. 2) Chemotherapy and/or total body irradiation has toxicities.

Rosenberg et al, Clin Can Res, 2011

Rx CR NMA 21/43 (49%) +2Gy 13/25 (52%) +12 Gy 18/25 (72%)

Adoptive Cell Therapy

TIL with Prior Lymphodepletion

Common Hurdle for Adoptive Cell Therapy

Facts:

1) Tumor reactive T cells can be difficult to obtain from all patients. 2) TIL therapy requires a resectable tumor. 3) Expansion of T cells to therapeutic numbers takes time. 4) Many cancers progress rapidly such that in many cases the patient can be too sick for adoptive T cell therapy.

Conclusions:

1) Despite the effectiveness of adoptive T cell transfer, this approach is only practical for some patients.

Gene Modified T Cell Therapy

Altering Antigen Specificity

Tumor cell

Antigenic Peptide MHC Class I β2M Surface Antigen

T-cell

CD3 TCR

α β

Gene Modified T Cell Therapy

Altering Antigen Specificity

Gene Modified T Cell Therapy

Altering Antigen Specificity – The Receptors

V C

H L

Immunoglobulin Chimeric Single Chain Antibody Receptor

scFv-Fcg scFv-CD3z

T Cell Receptor

a b z g e d z e CD3

Chimeric Activating Receptor

NKG2D-CD3z

Chimeric Ligand Receptor

IL-13-CD3z

Advantages

1) CAR T cells can be generated for any patient that has T cells in a short period of time (~10-20 days) 2) Recognizes antigens in an MHC- unrestricted fashion 3) Supersensitive, requires very low antigen expression 4) Can target non-protein antigens 5) Can engineer functional CD4+ and CD8+ T cells and non-T cells.

Disadvantages

1) CAR T cells can only recognize antigens expressed on the target cell surface 2) Associated with serious side effects, such as targeting normal cells expressing the target antigen 3) Risk of Cytokine Release Syndrome (CRS)

Gene Modified T Cell Therapy

Advantages and Disadvantages of CAR Therapy

Gene Modified T Cell Therapy

Altering Antigen Specificity - CAR

T-cell

CD3 TCR

α β pA

LTR

y+

LTR VL VH CD3ζ Linker CD3ζ VL VH CAR

Gene Modified T Cell Therapy

Altering Antigen Specificity - CAR

Tumor cell

Antigenic Peptide MHC Class I β2M Surface Antigen

T-cell

CD3 TCR

α β

CAR

Gene Modified T Cell Therapy

Altering Antigen Specificity - CAR

Tumor cell

Antigenic Peptide MHC Class I β2M Surface Antigen

T-cell

CD3 TCR

α β

Gene Modified Cell Therapy

Evolution of CAR

T-cell

CD3 TCR

α β

First generation CAR

z chain

Second generation CAR

z chain z chain CD28

Third generation CAR

OX40 CD28 4-1BB ICOS OX40 4-1BB ICOS

Gene Modified T Cell Therapy

CAR Targets

BCMA Multiple Myeloma CAIX Renal Cell CD19 Diffuse large B-cell lymphoma (DLBCL), Acute Lymphoblastic Leukemia (ALL) CD20 DLBCL, ALL, Mantle Cell Lymphoma (MCL) CD22 DLBCL, ALL, MCL, chronic lymphocytic leukemia (CLL) CD30 Hodgkins Lymphoma, Non-Hodgkin Lymphoma CD70 Pancreatic/Renal Cell/Breast/Ovarian/Melanoma CD171 Neuroblastoma CEA Colon GD2 Neuroblastoma GPC3 Hepatocellular Carcinoma Her-2 Breast/Ovarian Lewis-Y Acute Myeloid Leukemia (AML) Mesothelin Mesothelioma PSCA Prostate ROR1 CLL, MCL, ALL, Non-small Cell Lung Cancer, Triple Negative Breast Cancer

BCMA Multiple Myeloma CAIX Renal Cell CD19 Diffuse large B-cell lymphoma (DLBCL), Acute Lymphoblastic Leukemia (ALL) CD20 DLBCL, ALL, Mantle Cell Lymphoma (MCL) CD22 DLBCL, ALL, MCL, chronic lymphocytic leukemia (CLL) CD30 Hodgkins Lymphoma, Non-Hodgkin Lymphoma CD70 Pancreatic/Renal Cell/Breast/Ovarian/Melanoma CD171 Neuroblastoma CEA Colon GD2 Neuroblastoma GPC3 Hepatocellular Carcinoma Her-2 Breast/Ovarian Lewis-Y Acute Myeloid Leukemia (AML) Mesothelin Mesothelioma PSCA Prostate ROR1 CLL, MCL, ALL, Non-small Cell Lung Cancer, Triple Negative Breast Cancer

Gene Modified T Cell Therapy

CAR Targets

Gene Modified T Cell Therapy

Why CD19 as a CAR Target?

Frey, et al., Oncology, Vol 30, p.880-8, 890, 2016

Gene Modified T Cell Therapy

CD19 CAR - Clinical Trial Outcomes

Clinical Responses 1) Large numbers of objective clinical responses 2) Many responses are durable (CR) 3) Clinical responses found in most types of B cell malignancies 4) Clinical responses found in both adult and pediatric patients

Frey, et al., Oncology, Vol 30, p.880-8, 890, 2016

Gene Modified T Cell Therapy

CD19 CAR - Clinical Trial Outcomes

Serious Adverse Events 1) Cytokine release syndrome in all

• r most patients

2) Tumor lysis syndrome in some patients 3) Neurologic toxicity in some patients 4) Chronic B cell lymphopenia

Gene Modified T Cell Therapy

CD19 CAR – Commercial Trial Outcomes

Maude et al., N Engl J Med, 2018

• B cell ALL

– Results from multi-centered trials of centrally manufactured anti-CD19 CAR T cells have demonstrated a 70-93% completed response (CR) in relapsed or refractory B cell ALL. – In Aug 30, 2017, FDA approved Tisagenlecleucel for treatment of relapsed or refractory B cell ALL in patients up to 25 years of age. – Available follow-up data demonstrated that only 50% of patients remained in remission at one year.

Gene Modified T Cell Therapy

CD19 CAR – Commercial Trial Outcomes

• Large B cell lymphomas

– Results from multi-centered trials of centrally manufactured anti-CD19 CAR T cells have demonstrated 59-83% overall response rate (ORR) and 40-58% complete response (CR) in relapsed or refractory B cell lymphomas. – In Oct 18, 2017, FDA approved Axicabtagene ciloleucel for relapsed or refractory large B cell lymphomas. – In May 1, 2018, FDA expanded Tisagenlecleucel to include relapsed or refractory B cell lymphomas. – In a large trial, at median follow-up duration of 27.1 months, only 62%

• f patients remained in a CR and the majority of patients achieving

partial responses had progressed.

Locke et al., Lancet Onc, 2019

Gene Modified T Cell Therapy

Altering Antigen Specificity – The Receptors

V C

H L

Immunoglobulin Chimeric Single Chain Antibody Receptor

scFv-Fcg scFv-CD3z

T Cell Receptor

a b z g e d z e CD3

Chimeric Activating Receptor

NKG2D-CD3z

Chimeric Ligand Receptor

IL-13-CD3z

TCR α TCR β

pA

LTR

ψ+

LTR TCRβ TCRα

2A

Gene Modified T Cell Therapy

Altering Antigen Specificity - TCR

T-cell

CD3 Endogenous TCR

α β

Introduced TCR Mixed TCR

Gene Modified T Cell Therapy

Altering Antigen Specificity - TCR

Tumor cell

Antigenic Peptide MHC Class I β2M Surface Antigen

T-cell

CD3 TCR

α β

Gene Modified T Cell Therapy

Altering Antigen Specificity - TCR

Tumor cell

Antigenic Peptide MHC Class I β2M Surface Antigen

T-cell

CD3 Endogenous TCR

α β

Introduced TCR Mixed TCR CD34t

Gene Modified Cell Therapy

TCR Targets

CEA Colon gp100 Melanoma Her-2 Breast, ovarian, colon, lung HERV-E Renal hTERT Many human tumors MART-1 Melanoma MAGE-3 Melanoma and others MAGE-A4 Esophageal NY-ESO-1 Sarcoma, melanoma p53 Many human tumors PRAME Melanoma, AML, MDS, MM Tyrosinase Melanoma WT-1 ALL, AML, MDS

Group Target Disease Objective Response Rate

Aarhus, Denmark MART-1 melanoma 1/15 (7%) Duval et al, 2006 NIH/NCI MART-1 melanoma 2/15 (13%) Morgan et al, 2006 NIH/NCI MART-1 melanoma 6/20 (30%) Johnson et al, 2009 gp100 melanoma 3/16 (19%) NIH/NCI CEA Colorectal 1/3 (33%)* Parkhurst et al, 2011 NIH/NCI MAGE-A3 melanoma 5/9 (56%)* Morgan et al, 2013 U Penn/Adaptimmune MAGE-A3 myeloma and melanoma 0/2 (0%)* Linette et al, 2013; Cameron et al, 2013 NIH/NCI NY-ESO-1 synovial cell sarcoma 11/18 (61%) Robbins at al, 2015 melanoma 11/20 (55%) Mie, Japan MAGE-A4 esophageal 0/10 (3 with SD) Kageyama et al, 2015

Gene Modified Cell Therapy

TCR Clinical Trial Results

1) Unique Feature of our Clinical trials

1) Marker genes allow for purifying and tracking transduced T cells 2) Fresh cell products 3) Altered cytokines (growth factors) 4) Exact dosing of transduced T cells (CD34t expressing T cells per kg) 5) Deliver specific T cell subsets 6) Reduced Cost to the Patient

2) Two Phase I clinical trials have been initiated treating patient at three sites

1) HLA-A2 restricted, tyrosinase reactive TCR for melanoma patients at Loyola and Portland Providence 2) HLA-A11 restricted, HERV-E reactive TCR for renal cell carcinoma patients at the NHLBI/NIH

3) Three more Phase I Trials are near starting or in process

1) Various CD19 CAR constructs for B cell lymphomas 2) IL-13 CAR for glioblastoma 3) HLA-A2 restricted, hTERT reactive TCR for pancreatic cancer and other solid tumors

Gene Modified Cell Therapy

Loyola Experience

T-cell

CD3 TCR

α β

TCR α TCR β

pA

LTR

ψ+

LTR TCRβ CD34t TCRα

2A 2A

CD34t

Gene Modified Cell Therapy

Altering Antigen Specificity TCR

CD34t

CD3ζ VL VH CAR

Ψ+

LTR VL VH CD3ζ

pA

LTR CD34t

2A

TCR α TCR β

pA

LTR

ψ+

LTR TCRβ CD34t TCRα

2A 2A

CD34t

Gene Modified Cell Therapy

Altering Antigen Specificity TCR

CD34t

CD3ζ VL VH CAR

Ψ+

LTR VL VH CD3ζ

pA

LTR CD34t

2A

T-cell

CD3 Endogenous TCR

α β

Introduced TCR Mixed TCR CD34t

Gene Modified Cell Therapy

Enriching for TCR Transduced T Cells

CD34 Vβ12 TRP-1 merge DAPI CD3 biopsy. biopsy.

Moore et al, Cancer Immunol. Immunother, 2018

Gene Modified Cell Therapy

Dose Level I – Patient 2&3

0.01 0.1 1 10 100 10 20 30 40 0.01 0.1 1 10 100 10 20 30 40 0.01 0.1 1 10 100 45 145 245 345 445 545 0.01 0.1 1 10 100 45 145 245 345 445 545

%CD34+ Cells Days Post-infusion

Dose Level TIL 1383I TCR HERV-E TCR CD19 CAR

I 2.5x106 T cells/kg 1.0x106 T cells/kg 0.5x106 T cells/kg* II 7.5x106 T cells/kg 5.0x106 T cells/kg 1.0x106 T cells/kg III 25.0x106 T cells/kg 10.0x106 T cells/kg 1.5x106 T cells/kg IV 75.0x106 T cells/kg 50.0x106 T cells/kg 2.0x106 T cells/kg V 3.0x106 T cells/kg

Gene Modified Cell Therapy

Phase I Clinical Trial Doses

Patient TIL 1383I HERV-E

1 2.0x108/CD34+ T cells - NR 1.06x108/CD34+CD8+ T cells - SD 2 2.86x108/CD34+ T cells - PR* 8.25x107/CD34+CD8+ T cells - SD 3 2.06x108/CD34+ T cells - MR* 7.58x107/CD34+CD8+ T cells - PD 4 5.79108/CD34+ T cells - NR 5 8.42x108/CD34+ T cells - NR 6 5.90x108/CD34+ T cells - NR 7 1.76x109/CD34+ T cells - NR

Gene Modified Cell Therapy

Phase I Clinical Trial Outcomes

R Axillary LN April 2, 2014 Day -15 May 15, 2014 Day +28

Moore et al, Cancer Immunol. Immunother, 2018

Gene Modified Cell Therapy

Dose Level I – Patient 2

R Apical Lung Nodule April 2, 2014 Day -15 May 15, 2014 Day +28

Moore et al, Cancer Immunol. Immunother, 2018

Gene Modified Cell Therapy

Dose Level I – Patient 2

R Minor Fissure Lung Nodule April 2, 2014 Day -15 May 15, 2014 Day +28

Moore et al, Cancer Immunol. Immunother, 2018

Gene Modified Cell Therapy

Dose Level I – Patient 2

L Chest Subcutaneous Nodules April 2, 2014 Day -15 May 15, 2014 Day +28

Moore et al, Cancer Immunol. Immunother, 2018

Gene Modified Cell Therapy

Dose Level I – Patient 2

Gene Modified Cell Therapy

Dose Level I – Patient 2

Pre-treatment baseline Day 60 post HERV-E T-cell treatment

Clinical Resolution of Chest pain Decreased rib metastasis SUV

Gene Modified Cell Therapy

Summary

1) Gene modified cells are here to stay 2) The process of genetically modifying T cells leads to a safe and effective product 3) T cells can be genetically modified to recognize almost any target 4) Adoptive transfer of CAR and TCR transduced T cells can lead to

• bjective clinical responses

5) Adoptive transfer of CAR and TCR transduced T cells 6) Strategies are being developed to better predict if a CAR or TCR will target normal cells and use questionable ones more safely