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Leveraging CD26high Meso-CAR T cells in patients with advanced pancreatic cancer

Award Number: R01CA287866
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2024
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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Leveraging CD26high Meso-CAR T cells in patients with advanced pancreatic cancer - PROJECT SUMMARY This project translates an innovative, chimeric antigen receptor (CAR) T cell therapy to patients with pancreatic ductal adenocarcinoma (PDAC). We posit efficacy of CAR T targeting mesothelin (relevant PDAC antigen) can be enhanced by use of 1) a new subset expressing CD26 (a costimulatory molecule with enzymatic properties) termed CD26+ T cells; and 2) an innovative expansion protocol that incorporates the phosphatidyl inositol kinase-3 inhibitor (PI3Ki), duvelisib to improve CART persistence and metabolism. Our team reported that CD26+CD4+ T cells redirected with a Meso-CAR were polyfunctional and elicit activity against PDAC tumors in mice. Our overall hypothesis is that PI3Ki-expanded, CD26+CD4+ T cells are an ideal template for safely redirecting immunity to PDAC. While CD26+CD4+ T cells are polyfunctional, they fully differentiate after expansion, which reduces potency. However, our data shows CD26+T cell differentiation can be reduced using duvelisib during manufacturing, thus sustaining self-renewal (i.e., “stemness”), while enhancing in vivo cytolytic activity against orthotopic KPC tumors. This Project pursues three specific aims. Aim 1 will test our hypothesis that CD26+CD4+ CAR T cells degrade chemokines that induce suppressive myeloid cells, favorably altering the cell composition in the tumor microenvironment using relevant murine PDAC models (orthotopic and metastatic) in immune competent mice. Functional impact of Meso-CAR T on endogenous T cells will be tested in parallel studies in RAG2 KO to further define mechanism of efficacy. Aim 2 will investigate the interaction between Duvelisib-expanded CD26+CD4+ CAR T cells and conventional CAR T cells in targeting PDAC. Also, the role of CD26 in efficacy will be evaluated by using CD26+CD4+ MesoCAR T cells expressing enzymatically active or inactive CD26 or treating mice with a selective CD26 inhibitor (sitagliptin). The effect of CD26 enzyme modulation on the recruitment of myeloid cells in the PDAC TME will be tested in both human and murine in vivo systems. In Aim 3, we conduct a novel first-in-human trial in patients with advanced PDAC to evaluate safety, persistence, and fate of co-infused Duvelisib-expanded CD26+CD4+ and conventional CD3+ Meso CAR T cells. We will refine manufacturing and generate foundational feasibility/reproducible CMC data for an IND application. A phase 0/1 clinical trial will use low dose numbers of Duvelisib-expanded CD26+CD4+ Meso-CAR T cells, followed by dose escalation of Duvelisib-expanded CD26+CD4+ Meso-CAR T cells in combination with differentially bar-coded conventional CD3+ Meso-CAR T cells to define safety and clinically effective dose of this novel ACT therapy. Engraftment and persistence of CAR T products in blood and patient tumor biopsies will be tested with spatial molecular imaging and multi-parameter flow cytometry to study CART's metabolic/effector properties. Collectively, this work will define properties of novel Duvelisib-expanded CD26+CD4+ CAR T cells in animal PDAC models and determine safety and persistence of CD26+CD4+ CAR T cells in patients. Our results will enable subsequent trials with CD26+CD4+ Meso-CAR T cells as an individual therapy or a component of combined cell therapy in PDAC.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $575,037 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	3	2/9/2026	NON-COMPETING CONTINUATION	$575,037
														Subtotal = $575,037

Issue Date FY: 2025 ( Subtotal = $638,929 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	2	1/7/2025	NON-COMPETING CONTINUATION	$575,035
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	001	2	5/29/2025	NON-COMPETING CONTINUATION	$63,894
														Subtotal = $638,929

Issue Date FY: 2024 ( Subtotal = $575,241 )
2024	2024	EMORY UNIVERSITY	201 DOWMAN DR	ATLANTA	GA	30322	DEKALB	USA	Cancer Treatment Research	000	1	1/31/2024	NEW	$575,241
														Subtotal = $575,241

Grand Total All Awards = $1,789,207

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Leveraging CD26high Meso-CAR T cells in patients with advanced pancreatic cancer

Award Number: R01CA287866

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 02/01/2024

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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