Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma

Abstract

Purpose Transforming growth factor-β (TGF-β) production in the tumor microenvironment is a potent and ubiquitous tumor immune evasion mechanism that inhibits the expansion and function of tumor-directed responses; therefore, we conducted a clinical study to discover the effects of the forced expression of a dominant-negative TGF-β receptor type 2 (DNRII) on the safety, survival, and activity of infused tumor-directed T cells. Materials and Methods In a dose escalation study, eight patients with Epstein Barr virus-positive Hodgkin lymphoma received two to 12 doses of between 2 × 10 and 1.5 × 10 cells/m of DNRII-expressing T cells with specificity for the Epstein Barr virus-derived tumor antigens, latent membrane protein (LMP)-1 and LMP-2 (DNRII-LSTs). Lymphodepleting chemotherapy was not used before infusion. Results DNRII-LSTs were resistant to otherwise inhibitory concentrations of TGF-β in vitro and retained their tumor antigen-specific activity. After infusion, the signal from transgenic T cells in peripheral blood increased up to 100-fold as measured by quantitative polymerase chain reaction for the transgene, with a corresponding increase in the frequency of functional LMP-specific T cells. Expansion was not associated with any acute or long-term toxicity. DNRII-LSTs persisted for up to ≥ 4 years. Four of the seven evaluable patients with active disease achieved clinical responses that were complete and ongoing in two patients at > 4 years, including in one patient who achieved only a partial response to unmodified tumor-directed T cells. Conclusion TGF-β-resistant tumor-specific T cells safely expand and persist in patients with Hodgkin lymphoma without lymphodepleting chemotherapy before infusion. DNRII-LSTs can induce complete responses even in patients with resistant disease. Expression of DNRII may be useful for the many other tumors that exploit this potent immune evasion mechanism.

TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

“…In light of the recently reported clinical utility of shielding adoptive T‐cell therapies from TGF‐β, further exploration of TGF‐β countermeasures are warranted. We previously demonstrated that TGF‐β–binding CARs can be engineered to rewire Teff cells to proliferate and produce immunostimulatory cytokines in response to soluble TGF‐β, effectively inverting an immunosuppressive signaling molecule to a potent T‐cell stimulant that triggers immunosupportive functions .…”

“…For example, monoclonal antibodies targeting TGF‐β and TGF‐β receptor chain 2 (TGFBR2) have been extensively studied in preclinical and early‐phase clinical studies . Other studies have more specifically targeted TGF‐β signaling within the tumor microenvironment with a TGF‐β dominant‐negative receptor (TGF‐β DNR), which renders transduced tumor‐specific T cells unresponsive to TGF‐β . We recently described a novel CAR that responds to TGF‐β (TGF‐β CAR), demonstrating the ability to not only inhibit endogenous TGF‐β signaling in T cells but also convert TGF‐β into a potent T‐cell stimulant .…”

Switching on the green light for chimeric antigen receptor T‐cell therapy

“…35 Chimeric antigen receptor T cells have also been modified to express immune-stimulatory molecules to influence their interaction with other cell types within the local TME. 39 Overall, these studies suggest that therapeutic responses against solid tumors can potentially be augmented by engineering CAR T cells to express additional mediators that boost their local effector function and alter their interaction with surrounding cells in the TME. Furthermore, CD40 ligand directly engaged CD40-expressing tumor cells to alter their immunogenicity through the upregulation of surface receptors including MHC molecules and Fas ligand.…”

Off the shelf T cell therapies for hematologic malignancies

“…CAR-T cells containing multiple gene edits that include knockout of inhibitory signaling receptors such as PD-1 (PDCD1) [29,30], LAG-3 [31], or knock-in of a dominant negative TGFβ2R (TGFBR2) [32] have been described and are expected to enter into clinical trials in the near future.…”