CD5 CAR T-Cells for Treatment of Patients with Relapsed/Refractory CD5 Expressing T-Cell Lymphoma Demonstrates Safety and Anti-Tumor Activity

Abstract

We describe a Phase I dose escalation study (NCT03081910) of autologous CD5-directed CAR T cells as treatment of relapsed or refractory (r/r) T cell malignancies. CD5 is a pan-T cell marker present in ∼85% of T cell malignancies. Establishing a CAR T platform to target neoplasms of T cell origin has been hindered by shared expression of targetable antigens on both malignant and normal T cells promoting CAR T cell fratricide. We developed a second-generation CD5-specific CAR with CD28 co-stimulation that produces minimal and transient fratricide in T cells. The study was designed to evaluate the safety and feasibility of CD5 CAR T cells in patients with r/r T-cell malignancies as a bridge to allogeneic HSCT. Here we present our findings in patients with r/r non-Hodgkin T cell lymphoma (T-NHL).We have treated 5 patients (62-71 yrs) with CD5+ r/r T-NHL on dose levels 1 and 2 (1 × 107 and 5 × 107 CAR T cells/m2). All patients were heavily pretreated, with a median of 4 (range 2 -18) prior lines of therapy. One patient had previously failed allo-HSCT. All patients were transplant-eligible with an identified donor. Patients received cytoreductive chemotherapy with Cy/Flu followed by infusion of CD5 CAR T cells. We evaluated adverse events, clinical responses, and expansion/persistence of CAR T cells post-infusion.Two patients received CD5 CAR T cells on dose level 1 and 3 on dose level 2. CAR T cells reached peak expansion in peripheral blood (PB) 1-4 weeks after infusion. CD5 CAR T cells were detected in lymph nodes in 2 patients who underwent biopsies following treatment. PB CD3+ cell numbers were transiently reduced after cytoreduction and CAR T cell infusion, but ablation was never complete. CRS occurred in 3/5 patients (all at DL2). Grade 1 CRS was observed in 2 patients, and 1 patient had Grade 2 CRS and Grade 2 neurotoxicity, which resolved after treatment with tocilizumab and supportive care, respectively. Two patients experienced prolonged cytopenias at 6 weeks, one of whom also had reactivations of CMV and BK virus requiring antiviral therapy. On disease re-evaluation 4-8 weeks post-CD5 CAR T cell infusion, 3 of 5 evaluable patients obtained an objective response (1 on DL1 and 2 on DL2).Complete responses (CR) were achieved in 1 patient with angioimmunoblastic T cell lymphoma (AITL) and 1 with peripheral T cell lymphoma (PTCL) (Figure 1). Another patient with extensive AITL was classified as a mixed response due to the appearance of a new PET-avid lesion with resolution of remaining lesions (Figure 2). This patient received a 2nd infusion, proceeded to HSCT and remains in CR 6 mons post-transplant.These results demonstrate that CD5 CAR T cells are safe and can induce clinical responses in heavily treated patients with r/r CD5+ T-NHL without inducing complete T-cell aplasia. Importantly, elimination of malignant T cells by CD5 CAR T cells may allow previously ineligible patients to proceed to HSCT. We describe a Phase I dose escalation study (NCT03081910) of autologous CD5-directed CAR T cells as treatment of relapsed or refractory (r/r) T cell malignancies. CD5 is a pan-T cell marker present in ∼85% of T cell malignancies. Establishing a CAR T platform to target neoplasms of T cell origin has been hindered by shared expression of targetable antigens on both malignant and normal T cells promoting CAR T cell fratricide. We developed a second-generation CD5-specific CAR with CD28 co-stimulation that produces minimal and transient fratricide in T cells. The study was designed to evaluate the safety and feasibility of CD5 CAR T cells in patients with r/r T-cell malignancies as a bridge to allogeneic HSCT. Here we present our findings in patients with r/r non-Hodgkin T cell lymphoma (T-NHL). We have treated 5 patients (62-71 yrs) with CD5+ r/r T-NHL on dose levels 1 and 2 (1 × 107 and 5 × 107 CAR T cells/m2). All patients were heavily pretreated, with a median of 4 (range 2 -18) prior lines of therapy. One patient had previously failed allo-HSCT. All patients were transplant-eligible with an identified donor. Patients received cytoreductive chemotherapy with Cy/Flu followed by infusion of CD5 CAR T cells. We evaluated adverse events, clinical responses, and expansion/persistence of CAR T cells post-infusion. Two patients received CD5 CAR T cells on dose level 1 and 3 on dose level 2. CAR T cells reached peak expansion in peripheral blood (PB) 1-4 weeks after infusion. CD5 CAR T cells were detected in lymph nodes in 2 patients who underwent biopsies following treatment. PB CD3+ cell numbers were transiently reduced after cytoreduction and CAR T cell infusion, but ablation was never complete. CRS occurred in 3/5 patients (all at DL2). Grade 1 CRS was observed in 2 patients, and 1 patient had Grade 2 CRS and Grade 2 neurotoxicity, which resolved after treatment with tocilizumab and supportive care, respectively. Two patients experienced prolonged cytopenias at 6 weeks, one of whom also had reactivations of CMV and BK virus requiring antiviral therapy. On disease re-evaluation 4-8 weeks post-CD5 CAR T cell infusion, 3 of 5 evaluable patients obtained an objective response (1 on DL1 and 2 on DL2). Complete responses (CR) were achieved in 1 patient with angioimmunoblastic T cell lymphoma (AITL) and 1 with peripheral T cell lymphoma (PTCL) (Figure 1). Another patient with extensive AITL was classified as a mixed response due to the appearance of a new PET-avid lesion with resolution of remaining lesions (Figure 2). This patient received a 2nd infusion, proceeded to HSCT and remains in CR 6 mons post-transplant. These results demonstrate that CD5 CAR T cells are safe and can induce clinical responses in heavily treated patients with r/r CD5+ T-NHL without inducing complete T-cell aplasia. Importantly, elimination of malignant T cells by CD5 CAR T cells may allow previously ineligible patients to proceed to HSCT. Figure 1, Figure 2.Figure 2(A) Week 4 post-treatment PET/CT showing flare vs persistent disease and (B) 8 week post-treatment PET/CT showing significant interval resolution of disease with one new FDG avid lesion in left medial thigh in patient with AITL.View Large Image Figure ViewerDownload Hi-res image Download (PPT)

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