Enhancing anti-tumor immunotherapy with an engineered XCL1 protein

The National Cancer Institute awarded Xlock Biosciences, Inc. $305,368 on August 3, 2026, under the Cancer Treatment Research program (CFDA 93.395) to develop an engineered XCL1 protein as a cancer vaccine adjuvant. The project, titled "Enhancing Anti-Tumor Immunotherapy with an Engineered XCL1 Protein," runs through July 31, 2027, with work performed in Muskego, Wisconsin.

The funded research addresses a limitation in current cancer immunotherapy: while checkpoint inhibitors and cancer vaccines show promise, they benefit only 20–40 percent of treated patients, often constrained by insufficient CD8+ cytotoxic T cell recruitment into tumors and off-tumor toxicity from existing adjuvants. Xlock's approach targets the chemokine receptor XCR1, expressed exclusively on dendritic cell subtypes responsible for antigen cross-presentation to effector cytotoxic T lymphocytes. By engineering a recombinant chemokine capable of recruiting XCR1-expressing dendritic cells as an immune adjuvant, the work aims to improve anti-tumor immune responses with greater cancer cell specificity. This represents a novel mechanism not currently targeted by existing cancer treatment vaccines or immunotherapies.

This is a Small Business Innovation Research Phase I award, reflecting the program's focus on expanding private-sector commercialization of federally funded innovations and small business participation in research and development.

Abstract

Cancer immune surveillance is an important process by which the immune system can identify and eliminate neoplastic or malignant cells. Cancer immunotherapy uses monoclonal antibodies, small molecule drugs, adoptive cell transfer, oncolytic viruses or tumor vaccines to reactivate the body's immune system, kill tumor cells, and prevent disease recurrence. Despite notable success in treating patients with liquid and solid cancers, the beneficial outcomes of cancer immunotherapy remain limited to 20%-40% of treated patients and are accompanied by acute and prolonged toxicities. Durable responses to immune checkpoint inhibitors are often limited by insufficient recruitment of CD8+ cytotoxic t cell (CTL) cells into the tumor and/or antigenic escape to evade killing. Cancer vaccines using tumor-specific antigens to stimulate potent CTL responses can improve outcomes for cancers that are refractory to existing immunotherapy drugs but require adjuvants to provoke needed innate immune activation. Current generations of adjuvants are severely limited by lack of cancer cell specificity and off-tumor toxicity. The chemokine receptor XCR1 is expressed solely on a subtype of dendritic cells responsible for antigen cross-presentation to effector ctls. Antigen cross presentation is a fundamental mechanism of anti-viral and anti-tumor immune responses and is not currently targeted by existing cancer treatment vaccines or other immunotherapies. Antigen cross presentation and activation of effector ctls is directed in part by the chemokine XCL1. Published and preliminary work demonstrate the utility of XCL1-derived proteins, alone or as fusion proteins with surrogate tumor antigen, as a cancer vaccine adjuvant. Xlock biosciences, INC. (XL) has engineered a recombinant chemokine capable of recruiting XCR1- expressing dendritic cells when used as an immune adjuvant in murine models of leukemia, melanoma, and colon cancer. In aim 1, XL will design and manufacture XCL1-variants with enhanced stability and greater XCR1 agonist potency than native XCL1 proteins. In aim 2, XL will test the hypothesis that engineered XCL1- proteins stimulate CTL recruitment and tumor regression in a murine model for human cancer. Murine models are essential for the proposed work as there are no new approach methodologies that can faithfully replicate the human immune response. An intact immune response is necessary for the proposed work examining anti-cancer vaccines. Completion of proof-of-concept studies in this proposal will position XL to develop engineered XCL1 proteins as next generation vaccine adjuvants for use in liquid and solid cancers.