CART-007: a license to kill Free

In this issue of Blood, Ghobadi et al report results from a multicenter phase 1/2 study of patients with relapsed/refractory (R/R) T-cell acute lymphoblastic leukemia (ALL)/lymphoma (LBL) who received 1 infusion of allogenic CD7-targeting chimeric antigen receptor (CAR) T cells (WU-CART-007) after either standard or enhanced lymphodepleting (LD) chemotherapy.¹ Responses were observed in the expansion cohort with enhanced LD chemotherapy, and infusions were associated with acceptable rates of toxicities. Despite the relatively small numbers reported, this study offers the promise of a new treatment option for patients with otherwise dismal outcomes.

The prognosis for patients with R/R T-ALL/LBL has not improved over the past few decades, mainly due to a lack of novel treatment options.^2,3 CAR T-cell therapy is effective in patients with R/R B-ALL but similar application in T-ALL/LBL has been beset by challenges.⁴ These mainly relate to the shared expression of CAR-targetable antigens in malignant and normal T cells leading to an unwanted ablation of both normal and therapeutic T cells.⁵ Further, patients with R/R T-ALL/LBL often have rapidly progressive disease limiting time available for collection and manufacturing, compounded by low numbers of healthy circulating T cells due to the intense pretreatment. Finally, contamination of the CAR T-cell product by circulating malignant T-ALL blasts remains a theoretical concern. A well-designed “off-the-shelf” product can address these manufacturing challenges and offer an immediate therapeutic option for patients.

CD7 is an excellent target for T-ALL/LBL with high and uniform expression in these malignancies but it is also expressed on normal T and natural killer (NK) cells. WU-CART-007 was manufactured using an off-the-shelf approach from healthy donors after CRISPR/Cas9-mediated deletion of TRAC and CD7 genes (to minimize T-cell receptor [TCR]-mediated alloreactivity and CAR-mediated fratricide, respectively) and lentiviral transduction with a second-generation, 4-1BB-costimulated CD7CAR. Residual αβTCR⁺ CAR T cells were removed at the end of manufacturing using magnetic beads, further reducing the risk of a product-induced graft-versus-host disease (GVHD). The CAR T-cell products were cryopreserved and shipped to participating centers in the United States and Europe.

Treatment with WU-CART-007 showed encouraging overall response rates. In the phase 1 dose-escalation portion of the study, 15 patients received WU-CART-007 after standard LD therapy consisting of a total of 90 mg/m² of fludarabine and 500 mg/m² of cyclophosphamide. In the phase 2 expansion portion, 13 patients were dosed at the recommended phase 2 dose (RP2D) of 900 million WU-CART-007 cells following enhanced LD, consisting of a total of 120 mg/m² of fludarabine and 1000 mg/m² of cyclophosphamide.

This was a high-risk cohort: patients had received a median of 4 lines of previous therapy, and ∼40% had relapsed following a previous allogeneic hematopoietic stem cell transplant (HSCT) and had high baseline disease burden. Despite this, among 23 response-evaluable patients, meaningful responses were noted with a composite complete remission (CRc) rate of 52.2% and objective response rate (ORR) of 65.2%. Among the 11 response-evaluable patients at RP2D, the ORR was 90.9% and the CRc rate was 72.7%, with similar responses for T-ALL and T-LBL. Eight patients transitioned to HSCT after WUCART-007 and remained in complete remission (CR) following count recovery, with 4 remaining in CR at the time of reporting. These results suggest the potential of WU-CART-007 to serve as a successful bridge to transplant.

However, there are also limitations to using an off-the-shelf approach. Immune rejection of infused cells shortens their functional persistence, and consolidative therapies are needed to maintain responses. WU-CART-007 expanded 2 weeks postinfusion with limited persistence, with expansion bolstered by use of enhanced LD that translated to superior antileukemic effects. Only patients that received a consolidative allogeneic HSCT achieved long-term responses, highlighting the short-lived benefit of this strategy. Further, CD7 expression was retained in 6 of 7 analyzed cases of relapsed leukemia, demonstrating the limited immune pressure exerted by the CD7-directed therapy.

Similar to other reports using off-the-shelf CAR T cells,⁶ the need for enhanced LD to reduce immune rejection also increased the risk of toxicities. In this study, infections were more frequently observed with enhanced LD with ∼20% of patients having grade 3 and 4 infections. Two of the 3 grade 5 events recorded were from invasive fungal infections, of which 1 occurred with enhanced LD. There is therefore a clear need for intense infectious monitoring, prophylaxis, and treatment strategies to be in place with use of this therapy. The use of enhanced LD was also associated with prolonged cytopenias lasting up to 90 days postinfusion.

On the other hand, the limited duration of WU-CART-007 activity allowed for a more rapid rebound of endogenous CD7⁺ T and NK cells, which were temporarily supplanted by the CD7⁻ subsets postinfusion. Consequently, there was no significant increase in infections beyond day 28, illustrating an advantage of short persisting CAR T cells in the treatment of T-cell malignancies, of minimizing the risk of long-term T-cell aplasia and its associated complications.

Overall, there was an acceptable risk of toxicities. Higher grades of cytokine release syndrome (CRS) and inflammatory toxicities were also seen at higher dose levels and in those receiving enhanced LD, but both grade 4 CRS events resolved in <14 days. There was 1 case of grade 2 acute GVHD that resolved with therapy.

Other clinical trials using CD7CAR T cells for T-ALL/LBL reported thus far have employed autologous, donor-derived, or off-the-shelf approaches.^7-10 Collectively, data from these clinical trials show potent antileukemic efficacy with an acceptable safety profile, suggesting that CAR T-cell therapy could be an effective treatment strategy for patients with RR T-ALL.

The current study using an off-the-shelf approach shows that WU-CART-007 can be an effective bridge to HSCT, thereby providing an option for patients who are in urgent need of therapy or for those with low T-cell counts. Future efforts to optimize safety of this product and understand optimal sequencing of therapies could allow for the promise of long-term cures for patients with R/R T-ALL.

Conflict-of-interest disclosure: M.M. has equity in March Biosciences and receives research support from Fate Therapeutics and March Biosciences; patent fees and royalties from Fate Therapeutics, March Biosciences, Beam Therapeutics; and consulting fees from March Biosciences, NKILT Therapeutics and Curie.bio. S.N. declares no competing financial interests.