Preclinical targeting of aggressive T-cell malignancies using anti-CD5 chimeric antigen receptor

Abstract

The outlook for T-cell malignancies remain poor due to the lack of effective therapeutic options. Chimeric antigen receptor (CAR) immunotherapy has recently shown promise in clinical trials for B-cell malignancies, however, designing CARs for T-cell based disease remain a challenge due to the shared surface antigen pool between normal and malignant T-cells. Normal T-cells express CD5 but NK (natural killer) cells do not, positioning NK cells as attractive cytotoxicity cells for CD5CAR design. Additionally, CD5 is highly expressed in T-cell acute lymphoblastic leukemia (T-ALL) and peripheral T-cell lymphomas (PTCLs). Here, we report a robust anti-CD5 CAR (CD5CAR) transduced into a human NK cell line NK-92 that can undergo stable expansion ex vivo. We found that CD5CAR NK-92 cells possessed consistent, specific, and potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells. Furthermore, we were able to demonstrate significant inhibition and control of disease progression in xenograft mouse models of T-ALL. The data suggest that CAR redirected targeting for T-cell malignancies using NK cells may be a viable method for new and complementary therapeutic approaches that could improve the current outcome for patients.

CAR-Expressing Natural Killer Cells for Cancer Retargeting

“…Approaches directed against this antigen face the same difficulties as CD7-directed approaches since CD5 is also a pan T-cell marker. Two studies showed that NK-92 expressing CD5-directed CARs were efficient in vitro against CD5-positive cell lines and primary tumour cells, and developed anti-tumour activity in vivo [33, 34]. Additionally, the use of anti-CD3 CAR-equipped NK-92 against primary peripheral T-cell lymphoma cells and T-cell leukaemia cell lines was investigated showing cytotoxic activity in vitro and against Jurkat cells in a xenogeneic mouse model [35].…”

T lymphocytes as therapeutic arsenal for patients with hematological malignancies

“…As a consequence, the FDA recently approved two commercial CAR-T cell therapies for relapsed/refractory B-ALL and relapsed/ refractory diffuse large B-cell lymphoma (DLBCL) (tisagenlecleucel) [101 & ,102] and for the second-line treatment of DLBCL (axicabtagene ciloleucel) [103 & ,104]. Their development is now being expanded and explored through other malignancies targeting CD5 [105] and CD7 [106] in T cell malignancies, FLT3, CD33, CD38, CD56, CD117, CD123, NKG2DL and Lewis-Y in AML [107], CD30 in Hodgkin lymphoma [108] or B-cell maturation antigen (BCMA) (breakthrough therapy designation by the FDA), CD19, CD38, CD138, TACI and SLAMF7 in multiple myeloma patients [109,110].…”

Adoptive immunotherapy with CAR modified T cells in cancer current landscape and future perspectives

“…This shared antigenicity can cause fratricide in CAR T cells, inhibiting their proliferation and viability, and leading to normal T cells depletion and deep impairment of host immunity. To avoid this drawback, an anti-CD5 CAR transduced into a human Natural Killer (NK) cell line was tested (59). This approach showed potent anti-tumor activity against a variety of T-cell leukemia and lymphoma cell lines as well as primary tumor cells, and was able to demonstrate significant inhibition of disease progression in xenograft mouse models of T-cell ALL.…”