A chemokine system to unleash T cells against solid cancer - Regenerate immune responses against tumor
The immune system harbors intrinsic capacity to fight malignancy. Tumor-specific T cells play a crucial role in combatting cancer by recognizing and killing malignant cells. To enhance tumor-specific immune responses, T cells can be redirected using genetically engineered receptors against tumor antigens. Clinical success of engineered chimeric antigen receptor (CAR)-T cell has been achieved for hematological malignancies. However, success of CAR-T cell therapy in treating solid tumors has been limited, since transferred CAR-T cells could not infiltrate and persist in the hostile tumor environment. To improve adoptive transfer of CAR-T cells against solid tumors, we initiated a study to learn from intrinsic cues that promote T cell infiltration and persistence in human solid tumors.
We joined forces with Karolinska Institutet and Umeå University (Sweden) to study solid cancer disease. Here, we unraveled chemotactic mechanisms in muscle-invasive bladder cancer (BC). BC is a solid tumor disease with poor prognosis, yet, T cell infiltration into the BC can resuscitate patients to reject the tumor. We addressed the question which signals in BC favor T cell trafficking to the tumor and intratumor expansion. In this approach, we identified a distinct Th1 chemokine (C1, see notes) as main driver of T cell infiltration at the tumor site. In-vitro, we found that protective T cell subsets expressed a C1-specific receptor variant (R1*) and functionally, R1*+ T cells enriched when targeted by the ligand C1. Strikingly, analyzing the novel R1*-C1 axis in the tumor, we could predict overall survival and successful response to therapy in BC-patients. We hypothesize that R1*-C1 is a T cell-activating pathway in cancer with therapeutic potential.
In this project, we continue this approach within our European translational group. We pursue two aims:
1) Understanding how C1 improves anti-tumor T cell function.
2) Setting up a new therapy via R1*+ CAR-T cells.
1) We want to test the use of C1 for in-vitro culture and potential clinical application. For this, we will study signaling induced by the R1*-C1 pathway by applying i) our established flow cytometry method on phosphorylation targets (e.g. STAT-proteins) ii) multiplex-mass cytometry (in-house available in the cytometry core facility) and iii) a unique DIGI-West approach (with Tübingen in the EU-network Reshape).
2) We address to select natively R1*-expressing T cells from human PBMC as a starting population for CAR-T cell production (nR1-CAR-T cells). Further, we plan to endow ex-vivo generated tumor-specific T cells with the genetically engineered receptor R1* (eR1-CAR-T cells). In addition, we intend to access HER2-specific CAR-T cell products that were previously applied against mamma carcinoma (with Baylor College of Medicine Houston, TX, USA). Here, we seek to verify if low expression of R1* in products correlates with poor response rates following adoptive therapy.
In this project, we aim to gain insights into the newly described R1*-C1 axis in human solid cancer by native pre-selection of R1*-expressing cells or R1*-engineering for CAR-T cell generation. Thereby, we employ novel therapeutic approaches to boost the efficacy of tumor-specific CAR-T cells to reach and survive in the solid cancer microenvironment.
(please note that the axis R1*-C1 represents a chemokine - chemokine receptor variant interaction that cannot be revealed here due to current patent filing for biomarker use)
Review on the principal topic
Martinez, M. & Moon, E. CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment. Front Immunol 10, 128 (2019). [PubMed]
Study from our group incl. methodology relevant for this project
Schmueck-Henneresse, M. et al. Peripheral Blood–Derived Virus-Specific Memory Stem T Cells Mature to Functional Effector Memory Subsets with Self-Renewal Potency. J Immunol 194, 5559–5567 (2015). [PubMed]