Cellular and antibody-based immunotherapies have revolutionized clinical oncology, but resistance continues to preclude greater use of such therapies. Now, data from a dose-escalation study reveal the potential to overcome the inhibitory levels of TGFβ in many tumours, using infusions of TGFβ-receptor negative T cells.

“We had already conducted a 50-patient study using T cells specific for the Epstein–Barr virus (EBV) latent membrane proteins (LMP1 and LMP2) to treat patients with EBV-positive lymphoma, including Hodgkin lymphoma (HL)”, explains first author Catherine Bollard, adding that: “Complete responses (CRs) were seen in approximately 50% of patients, although it was clear that the majority of patients with HL (who did not have an underlying immunodeficiency) were not achieving CRs.” The authors then modified their approach to generate LMP-specific T cells that lack sensitivity to TGFβ by transgenic expression of a dominant-negative form of TGFβ receptor2 (DNRII).

A total of eight patients with HL, seven of whom had relapsed disease, received transfusion with either autologous (in seven patients) or donor-derived (in one patient) TGFβ DNRII, LMP-specific T cells, with no lymphodepleting chemotherapy prior to administration. No acute or long-term toxicities were reported. Four of seven evaluable patients had CRs, with two patients in remission for >4 years.

“Remarkable clinical responses were observed in several patients, with no toxicities — in stark contrast to the experience with anti-CD19 chimeric antigen receptor T cells,” Bollard highlights. “Going forward, we are now using the TGFβ DNRII in T-cells specific for other tumours, such as melanoma, lung cancer and HPV-associated cancer that are known to use TGFβ as an immune evasion strategy,” adds senior author Cliona M. Rooney.