Enhanced antitumoral activity of the academic CAR-T ARI0002h against normal and low BCMA-expressing myeloma cells after incorporating a transmembrane CD28 domain

Background
B-cell maturation antigen (BCMA) is the main target for chimeric antigen receptor (CAR)-T cells in multiple myeloma (MM), demonstrating promising outcomes. However, unlike what happens with CART19 in lymphoblastic leukemia and non-Hodgkin’s…

Effective allogeneic natural killer cell therapy for pancreatic adenocarcinoma avails conserved activating receptors and evades HLA I-driven inhibition

Background
At diagnosis, ~80% of pancreatic ductal adenocarcinomas (PDAC) have metastasized. Relapse is thus common even among patients who undergo surgical resection, the only curative option. PDAC progresses rapidly, and existing immunotherapies hav…

Antigen-IL-2 CAR-enhancer drives CAR-T fate and stemness, enhancing antitumor efficacy across models independent of IL-2R{alpha}

Background
Limited durability of clinical responses remains a major challenge in chimeric antigen receptor (CAR)-T therapy. CAR-enhancers (CAR-Es), which fuse tumor antigens to interleukin (IL)-2 muteins, provide a targeted strategy to enhance CAR-T p…

Corticosteroids ameliorate CAR T-cell-induced cytokine-release syndrome without inhibiting multiple myeloma treatment

Background
Cytokine-release syndrome (CRS) is a common toxicity of chimeric antigen receptor (CAR) T cells. CRS is often treated with corticosteroids such as dexamethasone. Dexamethasone is also used to treat multiple myeloma. To model CRS after CAR T…

Harnessing tumor acidity: innovative lactic acid-responsive promoter enables precision control of CAR-T cell activity in solid tumors

Background
The acidic tumor microenvironment (TME) in solid tumors, driven by abnormal metabolism and lactic acid accumulation, suppresses chimeric antigen receptor-T (CAR-T) cell efficacy while posing safety risks from on-target, off-tumor toxicity (…

Dysregulated expression of the tumor suppressor p14ARF in cancer provides an effective target for TCR-T cell therapeutics

Background
The CDKN2A gene encodes two canonical tumor suppressors, p16INK4A and p14ARF, which safeguard cells from malignant transformation by inducing cell cycle arrest and apoptosis in response to aberrant growth signals. Paradoxically, many cancer…

MMP3 overexpression enhances CAR-T cell infiltration and antitumor activity in a CAF-enriched solid tumor model

Background
Chimeric antigen receptor (CAR) T cell therapy has shown remarkable success in hematologic malignancies but faces substantial challenges in solid tumors. One of the main obstacles is the extracellular matrix (ECM), which serves as the physi…

CD2 costimulation bridges potent CAR-induced cytolysis and durable persistence

Background
Current second-generation CAR T cell products rely on CD28 or 4-1BB costimulatory domains, additions that respectively favor rapid cytolysis or long-term persistence, but rarely both. Preclinical modeling and retrospective analysis have lin…

Trispecific targeting of T cells engineered with TCR mimic antibodies to limit antigen escape

Background
Antigen loss and tumor heterogeneity present significant challenges for successful immunotherapies. T-cell receptor (TCR)-based therapies rely on the recognition of epitopes derived from intracellular tumor proteins presented by major histo…

Mutant calreticulin enables potent and selective CAR-T cell therapy in preclinical models of myeloproliferative neoplasms

Background
The adoptive transfer of T cells engineered to express chimeric antigen receptors (CAR-T) has shown high efficacy and safety in treating various hematologic malignancies. However, many hematologic disorders, such as BCR::ABL1-negative myelo…

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