Adoptive cell therapy (ACT) with tumor-reactive T cells isolated from the blood or tumor, or engineered with T cell receptors (TCRs) or chimeric antigen receptors (CARs) by gene transfer, is providing new treatment options for patients with chemotherapy refractory malignancies. Developing effective ACT for common cancers such as breast and lung cancer represents an urgent unmet need, but has posed several obstacles. These include the identification of molecules expressed on tumor cells that can be targeted safely and the design of optimal CARs that both redirect T cells to recognize tumors and overcome the immunosuppressive local tumor microenvironment that interferes with T cell mediated tumor eradication. We have identified the receptor tyrosine kinase-like orphan receptor ROR1 as a promising target for CAR-T cell therapy of human malignancies, including refractory chronic lymphocytic leukemia, mantle cell lymphoma, triple negative breast cancer and non small cell lung cancer. We designed and optimized ROR1-specific CARs for recognition of ROR1 positive tumors in vitro and for efficacy in immunodeficient mice engrafted with human tumor xenografts, and demonstrated that transferring autologous ROR1 CAR-T cells in non-human primates was safe. We have developed a monoclonal antibody to identify patients that have ROR1 positive tumors and produced a clinical grade ROR1 CAR lentiviral vector. Thus, we are now poised to perform a first-in-human clinical trial targeting ROR1 in both hematologic malignancies and solid tumors and to develop next generation ROR1 CARs designed to improve safety and for superior function in the tumor microenvironment.
The specific aims are:
Aim 1 : To determine the feasibility and safety of targeting ROR1 with autologous CD8+ and CD4+ T cells engineered with a ROR1/4-1BB/CD3? CAR and formulated in a defined composition for patients with hematologic malignancies (Cohort A) and solid tumors (Cohort B).
Aim 2 : To evaluate CAR-T cell phenotype, function and trafficking to tumor sites in vivo, and determine potential mechanisms of tumor resistance.
Aim 3 : To evaluate novel ROR1 CAR designs that enhance selective tumor cell recognition and/or overcome negative signaling by PDL1.

Public Health Relevance

) Despite improvements in diagnosis and treatment, cancers that are refractory to chemotherapy remain a common cause of death. Immunotherapy, including the administration of antibodies that target malignant cells or immune checkpoints, and the adoptive transfer of tumor-reactive T cells provides a new option for patients with even the most refractory malignancies. We have identified ROR1 as a candidate target for immunotherapy on many human cancers and designed receptors that can redirect the patient's T cells to kill ROR1 positive tumors. In this proposal, we will treat patients with ROR1 positive cancers by adoptively transferring T cells that are genetically engineered to recognize ROR1, and design new receptors to improve efficacy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA114536-12
Application #
9319144
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Merritt, William D
Project Start
2005-04-01
Project End
2021-06-30
Budget Start
2017-07-01
Budget End
2018-06-30
Support Year
12
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
Salter, Alexander I; Ivey, Richard G; Kennedy, Jacob J et al. (2018) Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal 11:
Srivastava, Shivani; Riddell, Stanley R (2018) Chimeric Antigen Receptor T Cell Therapy: Challenges to Bench-to-Bedside Efficacy. J Immunol 200:459-468
Salter, Alexander I; Pont, Margot J; Riddell, Stanley R (2018) Chimeric antigen receptor-modified T cells: CD19 and the road beyond. Blood 131:2621-2629
Sommermeyer, D; Hill, T; Shamah, S M et al. (2017) Fully human CD19-specific chimeric antigen receptors for T-cell therapy. Leukemia 31:2191-2199
Pollack, Seth M; He, Qianchuan; Yearley, Jennifer H et al. (2017) T-cell infiltration and clonality correlate with programmed cell death protein 1 and programmed death-ligand 1 expression in patients with soft tissue sarcomas. Cancer 123:3291-3304
Sadelain, Michel; Rivière, Isabelle; Riddell, Stanley (2017) Therapeutic T cell engineering. Nature 545:423-431
Balakrishnan, Ashwini; Goodpaster, Tracy; Randolph-Habecker, Julie et al. (2017) Analysis of ROR1 Protein Expression in Human Cancer and Normal Tissues. Clin Cancer Res 23:3061-3071
Sommermeyer, D; Hudecek, M; Kosasih, P L et al. (2016) Chimeric antigen receptor-modified T cells derived from defined CD8+ and CD4+ subsets confer superior antitumor reactivity in vivo. Leukemia 30:492-500
Liu, Lingfeng; Sommermeyer, Daniel; Cabanov, Alexandra et al. (2016) Inclusion of Strep-tag II in design of antigen receptors for T-cell immunotherapy. Nat Biotechnol 34:430-4
Paszkiewicz, Paulina J; Fräßle, Simon P; Srivastava, Shivani et al. (2016) Targeted antibody-mediated depletion of murine CD19 CAR T cells permanently reverses B cell aplasia. J Clin Invest 126:4262-4272

Showing the most recent 10 out of 43 publications