Adoptive “Non-Engineered” T-Cell Therapy Shows Preliminary Efficacy in Lymphomas

Chimeric antigen receptor (CAR) T-cell therapies engineered to recognize and destroy CD19 antigens on the surface of lymphoma cells have revolutionized the treatment of diffuse large B-cell lymphoma (DLBCL), but these products require complex manufacturing processes, which can lead to delays in treatment. To overcome these challenges, researchers from Baylor College of Medicine and Texas Children’s Hospital are exploring “non-engineered” T-cell therapies that are easier to manufacture and able to target multiple antigens.

At the 2019 Transplantation & Cellular Therapy Meeting of the American Society for Blood and Marrow Transplantation and the Center for International Blood & Marrow Transplant Research, Ann M. Leen, PhD, from Texas Children’s Hospital, reported that this approach was safe and led to complete responses (CRs) in most patients enrolled in a small study.

Attendees browse posters at the 2019 TCT Meetings.

Unlike CAR T-cell therapies engineered with viral vectors, with this approach, researchers selectively expand a patient’s T cells in the laboratory, conferring them with the ability to target tumor cells, Dr. Leen explained.

She shared results for 33 patients who had been treated with this therapy:

  • 13 with Hodgkin lymphoma (HL)
  • 17 with aggressive non-Hodgkin lymphoma (NHL; including DLBCL, mantle cell lymphoma, and T-cell lymphoma)
  • 3 with indolent NHL (including follicular lymphoma and marginal zone lymphomas)

The investigators used peripheral blood–derived T cells that were expanded to target several tumor-associated antigens (TAAs): PRAME, SSX2, MAGEA4, NY-ESO-1, and Survivin. Targeting multiple antigens simultaneously, the authors noted, overcomes another challenge associated with CAR T-cell therapies that target a single antigen: the heterogeneity of hematologic malignancies and the possibility for tumor immune evasion.

After the cells were expanded in the lab, patients were infused with between 0.5×107 and 2×107 multiTAA T cells/m2. No participants received lymphodepleting chemotherapy.
Eighteen patients had disease that was in remission at the time of T-cell infusion and received multiTAA-specific T cells as adjuvant therapy to prevent relapse; of these, all but two maintained disease remission. Remission duration ranged from three to 42 months among responders.

The other 15 patients received multiTAA-specific T cells to treat active disease. All of these patients had heavily pretreated disease, the authors noted, and had been exposed to a median of four lines of prior therapy (range not provided).

Of this group, five patients had transient disease stabilization followed by disease progression and four had ongoing stable disease, ranging from three to 18 months after T-cell infusion.

The remaining six patients (3 with HL and 3 with DLBCL) had achieved CRs, according to PET assessment, that ranged from four to 41 months.

“These clinical responses correlated with the detection of tumor-reactive T cells in patient peripheral blood post-infusion, directed against both targeted antigens as well as nontargeted TAAs … indicating induction of antigen/epitope spreading,” the authors reported.

The researchers noted that no participants experienced infusion-related systemic or neurologic adverse events – which are commonly reported with CAR T-cell infusions.

“Infusion of autologous multiTAA-targeted T cells … has been safe,” they concluded, “and despite concerns that endogenous T cells directed against shared/cancer testis antigens would be of insufficient affinity to produce prolonged benefit, [our cells] were able to induce durable CRs.”

The findings of this study were limited by the small study population and single-center design.

The authors report relationships with Marker Therapeutics, which sponsored the study.

Reference

Carrum G, Lulla P, Tzannou I, et al. Targeting lymphomas using non-engineered, multi-antigen-specific T cells. Abstract #24. Presented at the Transplantation & Cellular Therapy Meetings of ASBMT and CIBMTR, February 20, 2019; Houston, TX.

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