Clinical Lymphoma, Myeloma & Leukemia, Vol.22, Suppl.2 - October 2022

S9 E XABS-107-NH L CAR T-Cell Therapy i n Hodgki n L y m pho m a Carlos A. Ra m os, M D 1, *, D a v id H. Quach, Ph D 1 , a n d Clio n a M. Roo n ey, Ph D 1 1 Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA *Correspo n di n g author: caramos@bcm.edu Keywords CD30, chimeric antigen receptor, cytokine release syndrome, graft-versus-host disease, alloreactivity Introduction Autologous chimeric antigen receptor (CAR) T-cell therapies targeting CD19 has proved effective for B-cell malignancies. We previously showed similar results for T cells expressing CD30- CAR (CD30.CAR-Ts) targeting Hodgkin lymphoma (HL): heavily pretreated patients with relapsed or refractory HL who received fludarabine-based lymphodepletion followed by CD30. CAR-Ts had a high rate of durable responses and an excellent safety profile, highlighting the feasibility of extending CAR-T cell therapies beyond CD19 malignancies. 1 The manufacture of individual patient-derived CAR T cells, however, is expensive, frequently unsuccessful, too time consuming to benefit acutely ill patients, and difficult to scale for large numbers of patients. “Off- the-shelf ” T-cell products that are banked from healthy donors would improve accessibility, allow rapid treatment, and reduce costs. The major obstacles to the success of allogeneic T cells are graft-versus-host disease (GVHD) and graft rejection, mediated by host and recipient alloreactive T cells, respectively. To prevent GVHD, we are using Epstein-Barr virus-specific T cells (EBVSTs), which have not produced GVHD in more than 300 recipients. On the other hand, CD30 will be upregulated by host alloreactive T cells when they encounter infused allogeneic CD30.CAR-EBVSTs. Consequently, they will become targets for the CD30.CAR EBVSTs, preventing rejection of the product. Our previous clinical studies (NCT0291 7 083, NCT01555892, and NCT00062868) have shown that CD30 CAR T cells can destroy CD30-positive lymphoma cells through their chimeric receptor, while EBVSTs can kill EBV-positive lymphoma cells through their native T-cell receptor (TCR). 1,2 Thus, once engrafted, banked CD30-CAR EBVST may kill both CD30-positive and EBV-positive lymphomas through their CAR and TCR, respectively, without causing GVHD and without rejection. Material and Methods To assess the safety and activity of banked CD30 CAR EBVSTs, we are treating patients with multiply relapsed or refractory CD30-positive lymphomas in a phase 1 dose escalation study using 4×10 7 , 1×10 8 or 4×10 8 CD30.CAR EBVSTs infused after lymphodepletion with cyclophosphamide and fludarabine. Although CD30.CAR killing is not human leukocyte antigen (HLA) restricted, selection of the CD30.CAR EBVST product for each recipient was based on the best HLA class I and class II match; this should allow endogenous EBV to boost the in vivo activity of CD30.CAR EBVSTs via their native TCRs, and augment reactivity in patients whose CD30-positive malignancies are also EBV- positive. Results We have treated 9 patients so far, all with Hodgkin lymphoma. Of these, 2 had an initial response to treatment but later relapsed and were then re-enrolled at a higher dose level, for a total of 11 enrollments. Patients had received a median of 5 prior therapies, including potentially high dose chemotherapy with autologous stem cell rescue, checkpoint inhibitors and brentuximab vedotin, and all had active disease at time of CAR-T cell infusion. Despite partial HLA match (ranging from 1 to 5 alleles), we have not observed any instances of GVHD. There were only 2 cases of grade 1 cytokine release syndrome (CRS) and no instances of immune- effector cell associated neurotoxicity syndrome (ICANS). Patients have been treated at all dose levels and at 6-week evaluation per Lugano criteria, 5 patients have had a complete response and 4 have had a partial response (overall response rate of 82%), with higher dose levels being associated with better responses. Despite tumor responses, there was no detectable expansion of transgene-positive T cells in peripheral blood. To determine if CD30.CAR-EBVSTs become tissue resident or are eliminated by alloreactive T cells, we are analyzing tumor samples. Additionally, we will continue to assess the safety, efficacy, and durability of these responses. Discussion and Conclusions Banked CD30.CAR EBVSTs can safely be given to allogeneic recipients and may cause significant tumor responses including complete remissions. These cells may be a suitable platform for other “off-the-shelf ” CAR T-cell therapies. References 1. Ramos CA, Grover NS, Beaven AW, et al. Anti-CD30 CAR-T Cell Therapy in Relapsed and Refractory Hodgkin Lymphoma. J Clin Oncol. 2020 Nov 10;38(32):3 7 94- 3804. 2. Heslop HE, Sharma S, Rooney CM. Adoptive T-Cell Therapy for Epstein-Barr Virus-Related Lymphomas. J Clin Oncol. 2021 Feb 10;39(5):514-524.