# Advancing Next Generation CAR-T cells for Renal Cell Carcinoma

> **NIH NIH R44** · CELLINFINITY BIO, INC. · 2024 · $400,000

## Abstract

Project Summary/Abstract
Renal Cell Carcinoma (RCC) accounts for approximately 90% of kidney cancers in adults. Despite the
advancements made in cytokine, immune checkpoint, and targeted therapies, the rate of complete remission is
low and nearly all patients with metastatic disease experience disease progression. CAR-T therapy showed
clinically curative outcomes in hematological malignancies. However, there are multiple roadblocks for CAR-T
efficacy in solid tumors. Our company and founder have developed novel unbiased large/whole-genome T cell
CRISPR screening approaches and identified several universal modifications that enhanced CAR-T efficacy
against several tumor models in mice. We have developed a novel unbiased loss-of-function (LOF) screen,
enabled by site-specific, high-throughput massive knock-in engineering platform. Through this unbiased
evolution platform, we have identified a key gene PRDM1 mutation (exon 3 deletion) that modifies the epigenetic
state of T cells and significantly enhances immune characteristics of CAR-T cells, including increased T cell
proliferation, reduced exhaustion with improved memory and persistence, and high intra-tumor infiltration. In
addition, we have exploited the endocytic feature of the cytotoxic T-lymphocyte associated antigen-4 (CTLA-4)
cytoplasmic tail (CT) to reprogram CAR-T function and substantially enhance CAR-T anti-tumor activity in vivo.
CAR-T cells with CTLA-4 CT fused to the CAR C-terminus exhibit a progressive increase in cytotoxicity under
repeated stimulation, accompanied by reduced production of proinflammatory cytokines.
ENPP3 is highly expressed in >90% RCC cases, and expression is highly restricted in normal tissues and
typically located apically in normal tissues and thus relatively inaccessible to CAR-T. We have generated and
screened multiple scFvs against ENPP3, developed ENPP3 gene-enhanced CAR-Ts, and showed promising in
vitro and in vivo results in our kidney cancer animal model with no toxicity.
The goal of this proposal is to evaluate whether the combination of CAR-CTLA4 tail fusion and PRDM1-exon 3
knockout (KO) results in superior CAR-T–activity against RCC tumor relative to either modification alone, and to
nominate the best performing ENPP3 CAR-T plus genetic modification(s) for IND and Phase 1 clinical trials.
Specifically, we will evaluate ENPP3 CAR-Ts with PRDM1 △exon3 alone (CIB-101), CTLA4 tail fusion alone
(CIB-102), both PRDM1 △exon3 + CTLA4 tail fusion (CIB-103), and CAR-T with no modifications (CIB-100). We
will select our final clinical candidate by performing side-by-side in vitro as well as pre-clinical in vivo evaluation
of CIB-100 to 103 (aim 1, phase1), followed by process development, GMP manufacturing, pre-clinical
development, and IND filing. These studies include efficacy, PK/PD, GLP toxicology, and pathology analysis on
our final autologous ENPP3 CAR-T clinical candidate (aim 2, phase 2). By the end of the study period, we
anticipate having selected ...

## Key facts

- **NIH application ID:** 11007712
- **Project number:** 1R44CA295407-01
- **Recipient organization:** CELLINFINITY BIO, INC.
- **Principal Investigator:** Premal Patel
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2024-09-18 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11007712

## Citation

> US National Institutes of Health, RePORTER application 11007712, Advancing Next Generation CAR-T cells for Renal Cell Carcinoma (1R44CA295407-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/11007712. Licensed CC0.

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