HIV-virus Inspires Effective Anti-Leukemia Therapy

Nirali N. Shah, MD Associate Research Physician

Pediatric Oncology BranchNational Cancer Institute

December 1, 2017

Disclosures

None

Educational Objectives

Provide an overview of CAR therapy

Review the current state of the art for CAR therapy in ALL

Discuss limitations to CAR therapy

What is a CAR? • Chimeric Antigen Receptor

• Customized receptor• Extracellular antigen-binding domain• Intracellular signaling domain of T cells

• Retains the functionality of a T-cells with the antigen recognition properties of antibody

Process of Making CAR T-Cells

Role for HIV?

• Retroviruses, in particular lentivirus, are particularly skilled at entering T-cells

• Used to introduce genetic material into a T-cell which is then incorporated into the host cell genome

• Modified virus used to introduce anti-leukemia targeted antigen recognition properties

Childhood ALL• Most commonly

diagnosed childhood cancer

• 2900 cases/year

• Relapsed refractory disease remains a therapeutic challenge

• Outcomes in the AYA population remain poor

Improved Survival by Study Era

Data courtesy of GH Reaman, H Sather, Children’s Oncology Group

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CD19 CAR• CD19 is a B-cell marker

• First used to target CLL (chronic lymphocytic leukemia)

• Associated with cytokine release syndrome

• First child treated in 2012

• Several centers had simultaneous clinical trials

Cytokine Release Syndrome

Lee/Mackall Blood 2014Brudno/Kochenderfer Blood 2017

CD19 CAR Clinical Updates

Maude et al. NEJM 201490% CR rate (not ITT)All with CRS

Lee et al. Lancet 201567% CR rate (ITT)All responders with CRS

Novartis sponsored global CD19 CAR registration trial (“ELIANA”)

82% (41 of 50) patients achieved CR65% CR on ITT

FDA Approval!!

August 30, 2017

October 18, 2017

Will CD19 CAR be “THE” Answer?

Not for Everyone

Antigen Loss

Fatal Neurotoxicity

(or CRS)

30-40% Relapse RateCAR-T in April 2012

Anti-CD22 CAR ConstructSecond generation CAR

Utilizes m971 anti-CD22 scFv

4-1BB/CD3-zeta signaling

Haso et al, Blood 2013

Phase I Study of Anti-CD22 CAR T-Cells: Dose-Dependent Response

*Progressive disease by peripheral blasts#MRD Negative CR

Fry, Shah et al, Nat Medicine 2017

Relapse Remains a Problem

Fry, Shah et al, Nat Medicine 2017

Future DirectionsSimultaneous multi-antigen targeting

Expanding to other disease subtypes and presentations AML Central nervous system disease Lymphoma

Solid Tumors and Brain Tumors

Exploring Toxicity

Acknowledgements Terry J. Fry Crystal L. Mackall Daniel ”Trey” Lee Rimas Orentas Bonnie Yates Cindy Delbrook Haneen Shalabi Maryalice Stetler-Stevenson Constance Yuan Pamela Wolters Dennis Hickstein Alex Freeman

Staci Martin David Stroncek Hahn Khuu Marianna Sabatino Haiying Qin Naoza Collins-Johnson Michael Pulsipher Paul Jarosinski Lori Wiener Sima Zadeh Joan Galil

Photo credit: Marvin Joseph/The Washington Postwashingtonpost.com

A special thanks to all our patients, particularly those who are no longer with us, their families and referring teams. Their memory lives on in our work.

https://www.washingtonpost.com/national/health-science/tantalizing-counterattack-offers-breakthrough-hope-for-children-with-leukemia/2016/09/30/cf19b15a-663a-11e6-be4e-23fc4d4d12b4_story.html?hpid=hp_rhp-top-table-main_kidscancerava-110pm:homepage/story

HIV-virus Inspires Effective Anti-Leukemia Therapy DisclosuresEducational Objectives Slide Number 4What is a CAR? Process of Making CAR T-CellsRole for HIV?Childhood ALLCD19 CARCytokine Release SyndromeCD19 CAR Clinical UpdatesFDA Approval!!Will CD19 CAR be “THE” Answer?Anti-CD22 CAR ConstructPhase I Study of Anti-CD22 CAR T-Cells: �Dose-Dependent ResponseRelapse Remains a ProblemFuture DirectionsAcknowledgements