detecting-inter-individual-contamination-mismatches-multiomics-next

Detecting Inter-Individual Contamination and Mismatches in Multiomics Next-Generation Sequencing Data

High-throughput processing of patient biosamples by next-generation sequencing and the comparison of molecular data with patient-level and sample-level ...

Roche Innovation Center Zurich, F. Hoffmann-La Roche Ltd

Adoptive T-cell therapy using chimeric antigen receptor-modified T cells (CAR-T therapy) has shown dramatic efficacy in patients with circulating lymphoma. However, eradication of solid tumors with CAR-T therapy has not been reported yet to be efficacious. In solid tumors, stroma destruction, due to MHC-restricted cross-presentation of tumor antigens to T cells, may be essential. However, CAR-Ts recognize antigens in an MHC-independent manner on cancer cells but not stroma cells. In this report, we show how CAR-Ts can be engineered to eradicate large established tumors with provision of a suitable CD28 costimulatory signal. In an HER2-dependent tumor model, tumor rejection by HER2-specific CAR-Ts was associated with sustained influx and proliferation of the adoptively transferred T cells. Interestingly, tumor rejection did not involve natural killer cells but was associated instead with a marked increase in the level of M1 macrophages and a requirement for IFNγ receptor expression on tumor stroma cells. Our results argue that CAR-T therapy is capable of eradicating solid tumors through a combination of antigen-independent stroma destruction and antigen-specific tumor cell targeting.

Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ.

Doubling down with CAR-T cell cancer immunotherapy: a two-step recognition circuit enables discrimination between target antigen high and low cancer cells.

Many biomarkers have been proposed to be predictive of response to anti-programmed cell death protein-1 (PD-1)/anti-programmed death ligand-1 (PD-L1) checkpoint inhibitors (CPI). However, conflicting observations and lack of consensus call for an assessment of their clinical utility in a large data set. Using a combined data set of clinical trials and real-world data, we assessed the predictive and prognostic utility of biomarkers for clinical outcome of CPI in non-small cell lung cancer (NSCLC).

Predictive biomarkers for PD-1/PD-L1 checkpoint inhibitor response in NSCLC: an analysis of clinical trial and real-world data.

Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues.

Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for biomarker development in cancer immunotherapies.

This study investigates the role of Fibroblast Activation Protein (FAP)-positive cancer-associated fibroblasts (FAP+CAF) in shaping the tumor immune microenvironment, focusing on its association with immune cell functionality and cytokine expression patterns.

Investigating the complex interplay between fibroblast activation protein α-positive cancer associated fibroblasts and the tumor microenvironment in the context of cancer immunotherapy.

This phase Ib trial evaluated fibroblast activation protein-α-targeted IL2 variant (FAP-IL2v), a novel immunocytokine engineered to minimize CD25-mediated toxicities, in combination with cetuximab, in patients with recurrent, unresectable, or metastatic head and neck squamous cell carcinoma (HNSCC).

Phase Ib Study of the Immunocytokine Simlukafusp Alfa (FAP-IL2v) in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma.

This study explored the combination of fibroblast activation protein (FAP) IL2 variant (FAP-IL2v), a novel immune-cytokine, with pembrolizumab in patients with advanced and/or metastatic melanoma.

Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma.

Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy for several tumor indications. However, a substantial fraction of patients treated with CPIs derive no benefit or have short-lived responses to CPI therapy. Identifying patients who are most likely to benefit from CPIs and deciphering resistance mechanisms is therefore essential for developing adjunct treatments that can abrogate tumor resistance.

Article	Year
Efficacy of CAR T-cell therapy in large tumors relies upon stromal targeting by IFNγ. Cancer research\| PubMed ID: 25297631	2014
Doubling down with CAR-T cell cancer immunotherapy: a two-step recognition circuit enables discrimination between target antigen high and low cancer cells. Signal transduction and targeted therapy\| PubMed ID: 34321457	2021
Predictive biomarkers for PD-1/PD-L1 checkpoint inhibitor response in NSCLC: an analysis of clinical trial and real-world data. Journal for immunotherapy of cancer\| PubMed ID: 36822668	2023
Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for biomarker development in cancer immunotherapies. Frontiers in immunology\| PubMed ID: 38558814	2024
Investigating the complex interplay between fibroblast activation protein α-positive cancer associated fibroblasts and the tumor microenvironment in the context of cancer immunotherapy. Frontiers in immunology\| PubMed ID: 39035007	2024
Phase Ib Study of the Immunocytokine Simlukafusp Alfa (FAP-IL2v) in Combination with Cetuximab in Patients with Head and Neck Squamous Cell Carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 39422604	2024
Phase Ib Study of Immunocytokine Simlukafusp Alfa (FAP-IL2v) Combined with Pembrolizumab for Treatment of Advanced and/or Metastatic Melanoma. Cancer research communications\| PubMed ID: 39895413	2025
Machine learning identifies clinical tumor mutation landscape pathways of resistance to checkpoint inhibitor therapy in NSCLC. Journal for immunotherapy of cancer\| PubMed ID: 40032600	2025

Jehad Charo

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