# Project 1: Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration in colorectal cancer

> **NIH NIH P01** · ROSWELL PARK CANCER INSTITUTE CORP · 2020 · $485,860

## Abstract

PROJECT 1: ABSTRACT
CTL infiltration of tumor microenvironments (TME) predicts prolonged survival of patients with colorectal
cancer (CRC). It also differentiates between the small subset of patients (<5%) with microsatellite instability-
high [MSI-H] CRC, who show high levels of intratumoral CTLs and respond to PD-1 blockade from the rest of
CRC patients who do not respond. Our preliminary data demonstrate that a) TLR3-based adjuvants induce
CTL-attracting chemokines selectively in tumor stroma, but not surrounding non-tumor tissues; b) that
combination of TLR3 ligands (such as rintatolimod) with IFNα synergistically induce high levels of CTL-
attractants uniformly in all tumor lesions; and c) that inclusion of COX2 blockers enhances specificity of CKM in
promoting CTL attraction but suppressing Treg attraction. The three-component chemokine-modulatory
regimen (CKM rintatolimod, IFNα celecoxib) enhanced intratumoral CTL accumulation, prolonged survival and
synergized with PD1- and PD-L1 blockers in inducing cures (> 150 day survival) in mice with i.p. MC38 tumors,
resistant to PD-1 blockade alone. We completed phase I evaluation of systemic (i.v) CKM in patients with liver-
metastatic CRC (NCT01545141), observing its very good tolerability and improved ratios of CTL-to-Treg
markers in TME (compared to our patients receiving standard care only). We propose to:
Aim 1. Evaluate the in-patient immunologic effectiveness of i.v.- administered CKM to promote local
CTL accumulation in liver-metastatic CRC lesions in phase IIa trial NCT03403634. Comparing pre- versus
post-treatment tumor biopsies of 12 patients with liver-metastatic CRC, we will test if systemic CKM will
abrogate the TME heterogeneity and uniformly increase CTL numbers in TMEs, but not in surrounding tissues.
Aim 2. Evaluate the immune and antitumor effects of sequential versus cyclic application of CKM and
PD1 blockade and the advantage of additional immunization for long-lasting anti-tumor benefit. In
preclinical studies, we will test the hypotheses that the CKM-attracted DCs, NK cells and T cells will a) promote
local and systemic tumor-specific immunity and b) will amplify the CKM-initiated intratumoral production of CTL
attractants in an IFNγ and TNFα-dependent mechanism, resulting in sustained conditioning of the TME for
continued antitumor activity of PD1 blockade, even in the absence of additional vaccination.
Aim 3. Perform a phase I/II trial to test the clinical activity of CKM combined with PD-1 blockade in
patients with microsatellite-stable (MSS) CRC. In phase I/II trial, we will evaluate the clinical efficacy (iORR;
iRESIST) of CKM/anti-PD-1treatment in 19 patients with MSS-CRC, traditionally resistant to immunotherapy.
Programmatic Role: The unique role of Project 1 is to evaluate the effectiveness, uniformity and tumor-
selectivity of systemically-applied CKM and develop CKM-based treatments with sustained anticancer effect.
Its success will provide us with a tool to exte...

## Key facts

- **NIH application ID:** 9869514
- **Project number:** 1P01CA234212-01A1
- **Recipient organization:** ROSWELL PARK CANCER INSTITUTE CORP
- **Principal Investigator:** Pawel Kalinski
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $485,860
- **Award type:** 1
- **Project period:** 2020-03-03 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9869514

## Citation

> US National Institutes of Health, RePORTER application 9869514, Project 1: Combinatorial adjuvants promote uniform and selective intratumoral CTL infiltration in colorectal cancer (1P01CA234212-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9869514. Licensed CC0.

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