{"id":3671,"date":"2026-10-08T09:00:00","date_gmt":"2026-10-08T13:00:00","guid":{"rendered":"https:\/\/www.insilens.com\/?p=3671"},"modified":"2026-10-08T19:55:28","modified_gmt":"2026-10-08T23:55:28","slug":"cd28-emerges-as-a-car-t-target-in-t-cell-malignancies","status":"publish","type":"post","link":"https:\/\/www.insilens.com\/?p=3671","title":{"rendered":"CD28 Emerges as a CAR T Target in T Cell Malignancies"},"content":{"rendered":"

\"\"<\/p>\n

Company<\/strong><\/p>\n

LMU Munich; University of Freiburg (academic)<\/p>\n

Event Type<\/strong><\/p>\n

Peer-reviewed preclinical study (Nature Communications)<\/p>\n

Modality<\/strong><\/p>\n

CRISPR-edited CAR-T (CD28 knockout)<\/p>\n

Asset<\/strong><\/p>\n

Anti-CD28 CAR-T constructs<\/p>\n

Target<\/strong><\/p>\n

CD28<\/p>\n

Disease Area<\/strong><\/p>\n

T-cell acute lymphoblastic leukemia; selected T-cell lymphomas<\/p>\n

Summary<\/h4>\n

A peer-reviewed Nature Communications study from LMU Munich, the University of Freiburg, and collaborators reports a fratricide-resistant anti-CD28 CAR-T strategy for T-cell acute lymphoblastic leukemia and selected T-cell lymphomas. CRISPR-mediated CD28 knockout enabled manufacture, and lead constructs produced antileukemic activity comparable with anti-CD7 CAR-T cells in xenograft models while sparing most CD8 T cells and NK cells in ex vivo immune-depletion assays.<\/p>\n

The work introduces a potentially differentiated target, but it remains preclinical. CD28 is broadly expressed on healthy T-cell subsets and long-lived plasma cells, one lead binding domain derives from the TGN1412 superagonist lineage, and antigen down-regulation occurred in one model. The translational thesis therefore depends on prospective control of cytokine risk, immune depletion, antigen heterogeneity, and genome-editing quality.<\/p>\n

The investigators found CD28 overexpression across many pediatric and adolescent T-ALL samples and uniform expression in defined nodal T-follicular-helper lymphoma subtypes. Because effector T cells also express CD28, the team used CRISPR-Cas9 knockout before CAR transduction to reduce fratricide. Knockout exceeded 90% in reported experiments, and two lead CARs expanded and killed T-ALL cells in vitro.<\/p>\n

In CCRF-CEM xenografts, anti-CD28 CAR-T cells prolonged median survival to 35 days, comparable with anti-CD7 CAR-T cells and above untransduced or anti-CD19 controls. Across pooled constructs, one lead achieved median survival of 36 versus 33 days for the other. In autologous PBMC co-cultures, anti-CD28 CAR-T cells preferentially depleted CD4 effector subsets, including Th2 and Th17 cells, while producing markedly less loss of CD8 T cells and no direct NK-cell depletion relative to anti-CD7 CAR-T cells.<\/p>\n

Deep Analysis<\/h4>\n

Target selection is the central problem in T-lineage CAR therapy because malignant and normal T cells share surface antigens. CD7-directed approaches can be active but may cause profound, durable T- and NK-cell depletion. CD28 offers a different expression gradient: malignant T cells and selected CD4 memory subsets can be CD28-high, whereas many CD8 T cells and NK cells are less affected. The paper\u2019s key contribution is not simply another CAR target; it is evidence that target distribution could reshape the immune-deficiency profile.<\/p>\n

That advantage is conditional. The immune-depletion experiments were short ex vivo co-cultures, not a human immune system under sustained CAR persistence. Preferential loss of Th2 and Th17 cells could still impair mucosal defense and immune regulation. CD28-positive long-lived plasma cells may be depleted, creating hypogammaglobulinemia and revaccination requirements. A bridge-to-transplant strategy may tolerate more immune injury than a stand-alone curative strategy, so clinical positioning will matter.<\/p>\n

The TGN1412 history requires explicit separation of formats. The 2006 cytokine storm resulted from systemic exposure to a CD28 superagonist antibody. A membrane-anchored CAR recognition domain has different geometry and pharmacology, and the study did not observe activation of bystander wild-type T cells in its co-culture assay. That experiment reduces but does not eliminate the risk. Human cytokine-release potential, tonic signaling, activation against normal tissue, and the consequences of low-level CD28 engagement require dedicated nonclinical models and conservative first-in-human dosing.<\/p>\n

Manufacturing adds two critical quality attributes: the fraction of residual CD28-positive effector cells after editing and the genomic integrity of the knockout product. Residual target-positive T cells could undergo fratricide or unpredictable activation. Off-target editing, chromosomal rearrangement, variable CAR copy number, and batch-to-batch potency must be characterized. A fully allogeneic product would add TCR and HLA engineering burdens; an autologous product avoids alloimmunity but retains cost and timing constraints.<\/p>\n

Competitive displacement is plausible only if CD28-directed therapy retains efficacy with materially faster immune reconstitution than CD7-directed products. The paper also observed reduced CD28 on relapsing cells in one model, showing a credible antigen-escape route. Prospective antigen-density thresholds and dual-target or sequential strategies may be needed.<\/p>\n

Company and Product Background<\/h4>\n

T-ALL is an aggressive leukemia of immature T cells. CAR-T development is difficult because most candidate antigens are also expressed on normal T cells, causing fratricide during manufacture and on-target depletion after infusion.<\/p>\n

The study used CRISPR-Cas9 to remove CD28 from donor T cells before expressing anti-CD28 CAR constructs. LMU University Hospital and the University of Freiburg were the principal clinical-academic affiliations. No human dosing, regulatory clearance, commercial license, or disclosed financing was reported with the paper.<\/p>\n

Signal Extraction<\/h4>\n
    \n
  • Verified facts: the work is peer reviewed and published online 8 October 2026; efficacy is limited to in vitro systems and xenograft models; anti-CD28 CAR-T cells matched anti-CD7 controls in selected models and caused narrower ex vivo lymphodepletion.<\/li>\n
  • Authors\u2019 claim: CD28 is an actionable target that may reduce immunosuppression relative to CD7. This is biologically supported but not clinically validated.<\/li>\n
  • Interpretation A: expression gradients permit effective tumor targeting while preserving useful immune compartments. Support includes the CD8 and NK sparing in co-culture and efficacy in three models. Contradiction: short assays and immunodeficient mice cannot model prolonged human immune depletion or infection risk.<\/li>\n
  • Interpretation B: CD28\u2019s normal-tissue biology and superagonist history make the therapeutic window too narrow. Support includes depletion of CD4 effector subsets, likely plasma-cell effects, and antigen loss in one model. Contradiction would be a controllable first-in-human safety profile with rapid immune reconstitution and durable molecular remissions.<\/li>\n<\/ul>\n

    InSilens Take<\/h4>\n

    The paper clears the bar for translational interest, not treatment readiness. Its best feature is a measurable differentiation hypothesis: preserve more CD8 T and NK function than CD7 targeting without sacrificing leukemia control. That hypothesis is clinically testable and could support academic translation, licensing, or startup formation.<\/p>\n

    Upgrade evidence includes reproducible activity in patient-derived models spanning antigen density, humanized safety studies, validated off-target and genomic-integrity packages, and a manufacturing process with near-complete CD28 knockout. Falsification would be broad healthy-T-cell activation, clinically relevant superagonism, rapid CD28-negative escape, prolonged immune deficiency comparable with CD7 targeting, or inconsistent product yield.<\/p>\n

    Signal Assessment<\/h4>\n

    Signal Importance: 4 of 5. Signal Direction: positive preclinical; translation uncertain. Confidence in Facts: high. Confidence in Interpretation: moderate to low.<\/p>\n","protected":false},"excerpt":{"rendered":"

    A peer-reviewed Nature Communications study from LMU Munich, the University of Freiburg, and collaborators reports a fratricide-resistant anti-CD28 CAR-T strategy for T-cell acute lymphoblastic leukemia and selected T-cell lymphomas. CRISPR-mediated CD28 knockout enabled manufacture,…<\/p>\n","protected":false},"author":1,"featured_media":3679,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[4],"tags":[583,1002,366,1000,1003,1001],"class_list":["post-3671","post","type-post","status-publish","format-standard","has-post-thumbnail","hentry","category-technology-modalities","tag-car-t","tag-cd28","tag-crispr","tag-lmu-munich","tag-t-cell-acute-lymphoblastic-leukemia","tag-university-of-freiburg"],"blocksy_meta":[],"_links":{"self":[{"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/posts\/3671","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.insilens.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3671"}],"version-history":[{"count":1,"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/posts\/3671\/revisions"}],"predecessor-version":[{"id":3682,"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/posts\/3671\/revisions\/3682"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.insilens.com\/index.php?rest_route=\/wp\/v2\/media\/3679"}],"wp:attachment":[{"href":"https:\/\/www.insilens.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3671"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.insilens.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3671"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.insilens.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3671"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}