Targeted off-the-shelf immunotherapy to treat refractory cancers

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Grant Award Details

Grant Type:

Quest – Discovery Stage Research Projects

Grant Number:

DISC2-09615

Investigator(s):

Name:

Dan S Kaufman

Institution:

University of California, San Diego

Type:

Disease Focus:

Blood Cancer, Cancer, Ovarian Cancer, Solid Tumors

Human Stem Cell Use:

Embryonic Stem Cell, iPS Cell

Award Value:

$1,936,936

Status:

Closed

Progress Reports

Reporting Period:

Year 3 NCE

Therapeutic options for cancer have markedly expanded in the past few years, especially in the area of immunotherapy. However, many malignancies remain refractory to even these newest treatments. Here, we aimed to advance use of human iPSC-derived natural killer (NK) cells as a standardized, off-the-shelf immunotherapy product to treat thousands of patients with refractory malignancies.

To this end, we have 1) successfully produced human iPSC-derived NK cells expressing anti- Frizzled7 (FZD7) CAR and tested their function in vitro; 2) constructed novel CAR constructs with enhanced NK cell signaling. These studies indicated that anti-FDZ7 CAR enhances NK cell degranulation and cytokine production, leading to more efficient killing of FDZ7-expressing ovarian cancer cell lines in vitro. However, constitutive expression of CAR in iPSC-NK cells prevented expansion of NK cells.

Therefore, we tested the Switchable CAR (sCAR) system developed by collaborators at Calibr, which provides a mechanism to precisely regulate CAR-mediated anti-tumor activity by titrating the amount of the soluble or injectable “switch”. We successfully engineered human iPSCs with anti-FDZ7 sCAR and derived sCAR-expressing NK cells. Again, these sCAR-iPSC-NK cells mediated improved killing of the target tumor cells in a switch-dependent manner. Current efforts are focused on resolving issues with scale-up of these cells and repeating these studies using a cell line consented for clinical use.

Killer immunoglobulin-like receptor (KIR)-ligand mismatches are an important consideration in selecting allogeneic donors for patients with cancer. KIRs can be inhibitory or activating based on their recognition of HLA class I molecules. We demonstrated that iPSC-NK cells do not require KIR expression to become licensed for anti-tumor activity in vitro, killing tumor targets regardless of KIR expression. This precludes the need to optimize KIR profiles on iPSC-NK cells for patients of differing HLA haplotypes.

Grant Application Details

Application Title:

Targeted off-the-shelf immunotherapy to treat refractory cancers

Public Abstract:

Research Objective

This project will use human pluripotent stem cells to produce a standardized, off-the-shelf immunotherapy using novel immune cells that are specifically targeted to cure otherwise lethal cancers.

Impact

Unlike current immunotherapies produced on a patient-specific basis, iPSC-derived immune cells are targeted to tumors with high specificity, no off-target effects and without need for patient matching

Major Proposed Activities

Produce novel human iPSC-derived natural killer (NK) cells expressing a specifically designed receptor (CAR) to more effectively and efficiently target and kill human ovarian and other cancer cells.
Engineer novel NK cell-specific CAR constructs with NK cell-specific intracellular signaling domains to enhance iPSC-NK cell activation upon recognition of ovarian cancer target cells.
Optimize anti-leukemia activity of iPSC-derived NK cells using defined iPSC-NK cell populations with differing receptor profiles that target specific tumor profiles.
Optimize iPSC-NK cell expansion using systems that can be rapidly translated into clinical cell production. This will ensure we efficiently produce enough targeted iPSC-NK cells for clinical trials

Statement of Benefit to California:

Cancer remains the second leading cause of death in California, the US and worldwide. Despite advances in many areas of cancer treatment including chemotherapy and even immunotherapy, outcomes for relapsed or refractory cancers remain dismal. Here, we will use human iPSCs as the basis to develop a novel targeted cell population that can serve as a universal cellular immunotherapy to better treat and cure cancers for potentially thousands of patients in California each year.

Publications

Stem Cells (2018): Concise Review: Human Pluripotent Stem Cells to Produce Cell-Based Cancer Immunotherapy. (PubMed: 29235195)
Exp Hematol (2019): Development of innate immune cells from human pluripotent stem cells. (PubMed: 30611869)
Stem Cells (2021): Human induced pluripotent stem cell-derived macrophages ameliorate liver fibrosis. (PubMed: 34460131)
Cell Stem Cell (2018): Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity. (PubMed: 30082067)
Semin Immunopathol (2019): Off-the-shelf cell therapy with induced pluripotent stem cell-derived natural killer cells. (PubMed: 30361801)