# Project 1: Immunotherapy of B cell lymphoma with NKT cells

> **NIH NIH P50** · BAYLOR COLLEGE OF MEDICINE · 2022 · $319,192

## Abstract

PROJECT SUMMARY / ABSTRACT
Despite remarkable progress achieved with chimeric antigen receptor (CAR)-expressing T cells in the treatment
of relapsed/refractory B lineage neoplasms, CD19-specific CAR (CAR.CD19) autologous T cell products are not
curative for more than half of B-NHL patients. The long-term goal of Project 1 is to develop a safe and effective
immunotherapy for B-NHL using both the natural and engineered properties of CD1d-restricted Va24-invariant
natural killer T cells (NKTs). Unlike polyclonal T cells, NKTs have natural antilymphoma activity via direct
cytotoxicity against CD1d+ lymphoblasts or/and by activation of other immune effectors; further, allogeneic NKTs
do not produce graft-versus-host disease (GvHD) and can be prepared as “off-the-shelf” products. During the
current project period, we have initiated a first-in-human phase I clinical trial of allo-CAR.CD19 NKTs
(NCT03774654) and have treated the first four patients. The therapy was well tolerated and produced objective
responses in three patients. However short persistence of CAR.CD19 NKTs in patient peripheral blood may
decrease durability of response. To protect the therapeutic NKTs from host-mediated rejection, we have
developed new CAR constructs that co-express artificial micro(mi)RNA (amiR), consisting of promoterless
miRNA frames with embedded shRNA sequences targeting B2M and the class II major histocompatibility
complex transactivator (CIITA). These CAR/amiR constructs produce a graded downregulation of HLA class-I
and class-II in CAR-NKTs making them resistant to allogenic T and NK cells. We have also found that CAR-NKT
therapeutic potency can be augmented by pharmacologic or transgenic regulation of LEF1 transcriptional activity,
which controls NKT cell functional fitness. We hypothesize that allo-CAR.CD19 NKTs will continue to be well
tolerated and effective against B-NHL; their therapeutic potency can be further increased via amiR-mediated
protection from immune rejection and via LEF1-mediated retention of their antitumor activity. The following three
specific aims will test our hypotheses: 1) to determine the safety, efficacy, and immunological activity of allo-
CAR.CD19 NKTs in B-NHL patients; 2) to produce cGMP allo-NKTs co-expressing CAR.CD19 with B2M and
CIITA amiRs and to determine the safety, efficacy, and immunological activity of allo-CAR.CD19/amiR NKTs in
B-NHL patients; 3) to evaluate the mechanism by which LEF1 controls NKT cell functional fitness and test the
therapeutic potency of NKTs co-expressing CAR.CD19 and LEF1 in pre-clinical B cell lymphoma models. The
ongoing and proposed studies are the first to rigorously evaluate the utility of NKTs as a novel cellular platform
for redirected “off-the-self” immunotherapy. If proven to be safe and effective, this approach will provide a
foundation for a cost-effective cell therapy platform for B-NHL and perhaps other types of cancer as well.

## Key facts

- **NIH application ID:** 10495077
- **Project number:** 2P50CA126752-16
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Leonid S Metelitsa
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $319,192
- **Award type:** 2
- **Project period:** 2007-09-11 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10495077

## Citation

> US National Institutes of Health, RePORTER application 10495077, Project 1: Immunotherapy of B cell lymphoma with NKT cells (2P50CA126752-16). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10495077. Licensed CC0.

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