Insights into the optimal combination strategies
to convert cold to hot tumors
2017 ICI Boston
Memorial Sloan Kettering Cancer Center
Prasad S. Adusumilli MD
Associate Attending and Deputy Chief, Thoracic Surgery
Member, Centers for Cell Engineering, Cellular Therapeutics &
Experimental Therapeutics
Combination therapy with CAR T cells and Checkpoint Blockade
CAR T-cell therapy for solid tumors
IMAGE:
Prasad Adusumilli Laboratory,
Memorial Sloan Kettering
Cancer Center
Combination therapy with CAR T cells and Checkpoint Blockade
Mesothelin is a solid tumor-associated antigen target
•
Cell-surface antigen (40 kDa
GPI-linked)1
•
Binds to CA125/MUC16,
promotes metastases2
1Mod.
2Mol.
Pathol. 2003
Cancer. 2006
Annual incidence
371,977
Annual prevalence
2,119,926
Morello A, Adusumilli PS. Cancer Discov 2016
Combination therapy with CAR T cells and Checkpoint Blockade
Mesothelin expression in solid tumors
Combination therapy with CAR T cells and Checkpoint Blockade
Mesothelin-targeted CARs
Chimeric antigen receptors
Morello A, Adusumilli PS. Cancer Discov 2016
Combination therapy with CAR T cells and Checkpoint Blockade
Intrapleural administration potentiates CAR T-cell efficacy
Adusumilli PS, Sadelain M.
Sci Transl Med 2014
CD4 dependent
additive efficacy
Combination therapy with CAR T cells and Checkpoint Blockade
Intrapleurally administered CAR T cells accumulate regionally
and circulate extrapleurally
CD3 IHC
Combination therapy with CAR T cells and Checkpoint Blockade
Adaptive resistance in CAR T cells
Adaptive resistence in solid tumor CAR T-cell therapy:

What are the kinetics of adaptive resistance in CAR T cells?

Does costimulatory domain matter?

Extrinsic strategies to combine with checkpoint blockade

Intrinsic strategies to combat adaptive resistance
Combination therapy with CAR T cells and Checkpoint Blockade
Dose- and costimulatory domain-dependent differential efficacy
Combination therapy with CAR T cells and Checkpoint Blockade
Equal quantitative persistence of M28z and MBBz CAR T cells
Combination therapy with CAR T cells and Checkpoint Blockade
Functional persistence differs between M28z and MBBz
Upregulated PD-1 and PD-L1/2
promotes adaptive resistance
Combination therapy with CAR T cells and Checkpoint Blockade
Adaptive resistance in CAR T cells
Adaptive resistence in solid tumor CAR T-cell therapy:

What are the kinetics of adaptive resistance in CAR T cells?

Does costimulatory domain matter?

Extrinsic strategies to combine with checkpoint blockade

Intrinsic strategies to combat adaptive resistance
Combination therapy with CAR T cells and Checkpoint Blockade
PD-1 checkpoint blockade rescues CAR T-cell efficacy
Combination therapy with CAR T cells and Checkpoint Blockade
Adaptive resistance in CAR T cells
Adaptive resistence in solid tumor CAR T-cell therapy:

What are the kinetics of adaptive resistance in CAR T cells?

Does costimulatory domain matter?

Extrinsic strategies to combine with checkpoint blockade

Intrinsic strategies to combat adaptive resistance
Combination therapy with CAR T cells and Checkpoint Blockade
PD-1 DNR: cell-intrinsic checkpoint blockade
Tumor re challenge
after one year
Control
M28zPD1DNR
Day 15
Cherkassky L, Morello A, Adusumilli PS
J Clin Inv 2016
Combination therapy with CAR T cells and Checkpoint Blockade
CAR T cells with checkpoint blockade
Extrinsic checkpoint blockade:

John LB, Darcy PK. Clin Cancer Res 2013

Blake SJP, Steptoe RJ. PLOS One 2015
Promotes T-cell migration
Intrinsic checkpoint blockade:

Shin JH, Choi K. Immune Network 2016

Su S, Liu B. Oncoimmunology 2017
Fusion receptor:

Prosser ME, Jensen MC. Mol Immunol 2012

Kobold S, Rothenfußer S. JNCI 2015
Reduces percentage of MDSCs
Combination therapy with CAR T cells and Checkpoint Blockade
Transforming cold solid tumors to hot and keep them warm
Adaptive resistence in solid tumor CAR T-cell therapy:

CAR T cells persist with upregulated PD-1

4-1BB relatively protects against PD-1 upregulation

Checkpoint blockade effective dose and regimen to be determined

PD-1 DNR is an effective strategy
Our next steps:
- Initiate a combination therapy clinical trial
- Translate PD1 DNR to a clinical trial
Combination therapy with CAR T cells and Checkpoint Blockade
PD-1 checkpoint blockade enhances CAR T-cell efficacy
Combination therapy with CAR T cells and Checkpoint Blockade
Acknowledgements
Grant Funding
Adusumilli Lab
Aurore Morello
Leonid Cherkassky
Miguel Lago-Lopez
Jonathan Villena-Vargas
Elliot Servais
Christos Colovos
Stefan Kachala
Adam Bograd
NCI:
Dimiter Dimitrov, Yang Feng
Sadelain Lab
Gertrude Gunset, Jason
Plotkin
CTC
Renier Brentjens, Shanu Modi
Elizabeth Halton, Claudia Diamonte
Center for Cell Therapy
Thoracic Surgery
& Cell Engineering
Thoracic Surgical attendings
Facility
Res Study Asst. (RSA)
Isabelle Riviere
Xiuyan Wang
Surgery
Peter Scardino
Murray Brennan
Alain Vincent
Joe Dycoco
Erin McGee, Daniel Ngai
Thanks to
Patient and
family members