[The Svedberg seminar] – Genome-scale screens to program new T cell states for next-generation immunotherapy
August 31, 2026 @ 15:15 – 16:15 CEST
Neville Sanjana
Professor New York University, USA
Bio
Neville Sanjana, PhD, is a Core Faculty Member at the New York Genome Center and Professor of Biology, Neuroscience and Physiology at New York University. Recent work from his lab identified synthetic cell programs to enhance cell and gene therapies and developed new methods to identify causal noncoding variants and their target genes at scale. Dr. Sanjana is a recipient of the Presidential Early Career Award for Engineers and Scientists, AAAS Wachtel Prize for Cancer Research, the NIH’s New Innovator Award, the Cancer Research Institute Technology Impact Award, the DARPA Young Faculty Award, the Kimmel Scholar Award, the MRA Young Investigator Award, and also is a Leichtung Family Investigator of the Brain and Behavior Foundation.
Genome-scale screens to program new T cell states for next-generation immunotherapy
The engineering of patient T-cells for adoptive cell therapies has revolutionized the treatment of several cancer types, but further improvements are needed to increase response and cure rates. T-cell–mediated anti-tumor immunity relies on potent cytotoxic effector function, whereas durable tumor clearance depends on stemness-driven long-term persistence. However, endogenous T-cell differentiation programs render these phenotypes mutually exclusive: Effector maturation physiologically depletes the stem-like reservoir. Chimeric antigen receptor (CAR) T cells, despite their impact on blood cancer treatment, remain bound by this intrinsic biological trade-off.
To identify new genetic programs for effective cell therapy, we overexpressed ~12,000 barcoded human open reading frames (ORFs) and measured their impact on proliferation of primary human CD4+ and CD8+ T-cells. When overexpressed, the top-ranked ORF, lymphotoxin beta receptor (LTBR), induced profound transcriptional and epigenomic remodelling, increasing T-cell effector functions, as well as resistance to exhaustion in chronic stimulation settings, via constitutive activation of the canonical NF-kB pathway.
Using this gene, we develop a novel CAR that decouples effector differentiation from the loss of stemness. Direct fusion of the intracellular domain of the T-cell proliferation driver LTBR to the CD3ζ tail induces a shared pro-inflammatory effector program in both CD4⁺ and CD8⁺ CAR T cells. In the CD4⁺ compartment, this effector differentiation is accompanied by an overlay of stemness-associated gene modules (TCF7 and LEF1), resulting in a superimposed state where pro-inflammatory and self-renewal programs coexist. This dual phenotype is dependent on the CAR configuration and is not recapitulated by LTBR co-expression. In CAR T cells engineered from diffuse large B-cell lymphoma (DLBCL) patients, the LTBR-fusion CAR sustains tumor suppression after several rounds of repetitive tumor challenge. This lineage-specific phenotype is consistent with clinical observations linking durable remissions to persistent, effector-competent CD4⁺ CAR T cells. Together, our CAR engineering approach overrides canonical T cell differentiation constraints to yield dysfunction-resistant therapies, elucidating the functional basis of lineage-specific CD4⁺ CAR T-cell responses.
Host: Sanja Vickovic sanja.vickovic@scilifelab.uu.se UU
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