Peripheral T cell lymphomas comprise a heterogeneous group of rare diseases, representing 10–15% of all non-Hodgkin lymphomas (NHLs). Upfront treatment for peripheral T cell lymphoma (pTNHL) includes CHOP-like (cyclophosphamide, adriamycin, vincristine, prednisone) multiagent chemotherapy with or without etoposide, followed by stem cell transplantation as consolidation in responsive fit patients. This approach induces durable long-term remission in approximately 40% of cases; early refractoriness during induction occurs in approximately 25% of patients, with the remaining patients typically relapsing within 24 months. With the exception of patients with anaplastic large cell lymphomas who are eligible to receive brentuximab vedotin, there is no standard of care in the relapse setting. In patients not eligible to receive high-dose chemotherapy followed by allogeneic stem cell transplantation, the prognosis is dismal.

CAR-T cells have shown impressive results in relapsed/refractory B-cell lymphoma and are currently under investigation in T cell lymphomas.

Target Antigens

The choice of the appropriate antigen constitutes the main challenge in targeting T cell malignancies using CAR-T cells. Many target antigens are expressed by both physiological T cells and engineered CAR-T cells (Tables 17.1 and 17.2).

Table 17.1 Pan-T cell antigens
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Table 17.2 Antigens with restricted expression
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Therefore, this shared antigen expression can potentially result in the following issues:

  • A fratricide effect on CAR-T cells.

  • Ablation of physiological donor T cells after CAR-T cell infusion, leading to deep and/or long-lasting immune deficiency and T cell aplasia.

CAR-T Development in T Cell Malignancies

Some experimentally engineered CAR-T cell products targeting CD5, CD7, CD30, and TRBC1 (T cell receptor beta chain 1) have been tested (Table 17.3).

Table 17.3 CAR-T cells targeting T lymphocyte antigens
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Key Points

  • Target antigens are expressed by normal T cells, malignant T cells, and engineered CAR-T cells.

  • Therefore, the major concern for targeting T cell malignancies with CAR-T cells is a fratricide effect.

  • A second major issue is the ablation of normal T cells after CAR-T cell infusion, potentially causing severe and/or long-lasting immune deficiency and T cell aplasia.

  • Currently, the most promising constructs are CAR-T cells targeting CD30.

  • Phase I and II studies are ongoing in T cell malignancies and Hodgkin lymphoma, thus far demonstrating feasibility, tolerability, and potential for clinical efficacy.