Tumor Immunology & Immunotherapy Group

Immunotherapies exploit the immune system to attack cancer. Clinical studies have shown that immune checkpoint inhibitors and T-cell-based therapies can mediate tumor regression in patients with metastatic disease. In addition to surgery, radiation therapy and chemotherapy, immunotherapy has therefore become the fourth pillar of cancer treatment. We focus on advancing insights into the naturally occurring T-cell response to cancer and establishing ways to exploit these antitumor responses to develop more effective and personalized immunotherapies.

Mounting evidence shows that neoantigens play an important role in the clinical efficacy of cancer immunotherapies. Thanks to the support received from the BBVA Foundation’s Comprehensive Program of Cancer Immunotherapy & Immunology – CAIMI-I and CAIMI-II, as well as other funding agencies, and through our group’s long-standing collaboration with Elena Garralda, Group Leader of VHIO’s Early Clinical Drug Development Group, and Director of our Research Unit for Molecular Therapy of Cancer (UTIM) – CaixaResearch, we are conducting a phase I clinical trial to evaluate the safety and tolerability of neoantigen-selected TILs.

This ongoing clinical trial is funded by the Instituto de Salud Carlos III – ISCIII (Carlos III Health Institute) and adopts a highly personalized approach (Figure) to screen for T-cell mediated recognition of mutated antigens. In this pilot study we aim to treat up to 10 patients with epithelial cancers and melanoma refractory to standard therapies. By enriching for neoantigen-reactive lymphocytes, we hope to extend the efficacy of TIL therapy beyond melanoma. In addition, our group is involved in several other clinical trials using non-selected ex vivo expanded TIL for the treatment of melanoma, germ cell cancers and tumors with mutations in the SWI/SNF complex.

One of our group’s strategic goals is to develop strategies that exploit the circulating tumor-reactive lymphocyte repertoire. We have shown that tumor-reactive T cells can frequently be detected circulating in the blood of cancer patients, irrespective of the specific tumor type. The ability to track and monitor tumor-reactive CD8+ and CD4+ T cells in blood has tremendous therapeutic potential, but this approach is more challenging due to the lower prevalence of these cells. We have contributed to defining a phenotypic signature that can guide the identification and enrichment of tumor and neoantigen-reactive T cells from the blood of cancer patients.

We have also demonstrated the use of circulating tumor DNA (ctDNA) to identify neoantigens, offering a minimally invasive approach to analyzing tumor-specific antigens. We are also developing a computational pipeline to conduct extensive profiling of the peripheral blood T-cell response at the single-cell level in patients treated with immune checkpoint inhibitors (ICIs) and vaccines to better understand the determinants of treatment response.

Our group is also interested in developing high-throughput technologies to better decipher the landscape of tumor antigens that increase cancer cells’ susceptibility to immune attack, and advance insights into shared neoantigens as well as mechanisms of resistance to T-cell cytotoxicity.