Selective, Off-the-Shelf Logic Gated CAR NK Cell Therapy Targeting CD33 and/or FLT3 Expressing Hematologic Malignancies
Grant Award Details
Grant Type:
Grant Number:
CLIN2-16156
Investigator(s):
Disease Focus:
Human Stem Cell Use:
Award Value:
$8,000,000
Status:
Active
Grant Application Details
Application Title:
Selective, Off-the-Shelf Logic Gated CAR NK Cell Therapy Targeting CD33 and/or FLT3 Expressing Hematologic Malignancies
Public Abstract:
Therapeutic Candidate or Device
SENTI-202 is an allogeneic off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cellular therapy targeting CD33 and/or FLT3 malignancies.
Indication
CD33 and/or FLT3 expressing hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Therapeutic Mechanism
SENTI-202 has been designed to incorporate a logic gated gene circuit and an engineered cytokine, all delivered through a single retrovirus: a bivalent activating CAR (aCAR) targeting CD33 and/or FLT3, a protective inhibitory CAR (iCAR) recognizing a cell surface protein endomucin (EMCN) on healthy hematopoietic stem & progenitor cells (HSCs/HPCs), and calibrated release IL15 (crIL15) to support NK cell signaling, activation and persistence.
Unmet Medical Need
AML and MDS have a grim prognosis and a profound unmet medical need. The ideal therapeutic should target cancer cells and protect healthy ones. SENTI-202 exhibits selective cytotoxicity against primary CD33 and/or FLT3 expressing AML/MDS patient-derived samples, while protecting primary HSCs.
Project Objective
Successful trial enrollment of ~24 subjects in Ph1
Major Proposed Activities
SENTI-202 is an allogeneic off-the-shelf chimeric antigen receptor (CAR) natural killer (NK) cellular therapy targeting CD33 and/or FLT3 malignancies.
Indication
CD33 and/or FLT3 expressing hematologic malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
Therapeutic Mechanism
SENTI-202 has been designed to incorporate a logic gated gene circuit and an engineered cytokine, all delivered through a single retrovirus: a bivalent activating CAR (aCAR) targeting CD33 and/or FLT3, a protective inhibitory CAR (iCAR) recognizing a cell surface protein endomucin (EMCN) on healthy hematopoietic stem & progenitor cells (HSCs/HPCs), and calibrated release IL15 (crIL15) to support NK cell signaling, activation and persistence.
Unmet Medical Need
AML and MDS have a grim prognosis and a profound unmet medical need. The ideal therapeutic should target cancer cells and protect healthy ones. SENTI-202 exhibits selective cytotoxicity against primary CD33 and/or FLT3 expressing AML/MDS patient-derived samples, while protecting primary HSCs.
Project Objective
Successful trial enrollment of ~24 subjects in Ph1
Major Proposed Activities
- GMP manufacturing and drug product release to supply the SENTI-202-101 Ph1 clinical trial
- Assess clinical safety, determine the recommended Ph2 dose, and evaluate preliminary efficacy of SENTI-202
Statement of Benefit to California:
SENTI-202 will benefit California patients with AML and MDS malignancies. In 2021, in California AML caused the death of 2 females and 3 males per 100,000 while MDS caused the death of 2 females and 2 males per 100,000. The incidence of AML and MDS are highest in the White population, but disparities impact survival in minority populations. We selected sites that have high percentages of Hispanic, Black, and Asian patients, such as Los Angeles (these comprise 58.4% of California’s population).