OFF‐THE‐SHELF CD30.CAR‐MODIFIED EPSTEIN‐BARR VIRUS‐SPECIFIC T CELLS (CD30.CAR EBVSTS) PROVIDE A SAFE AND EFFECTIVE THERAPY FOR PATIENTS WITH HODGKIN LYMPHOMA (HL)

Abstract

Off-the-shelf allogeneic T-cell therapies face the major challenges of graft-versus-host disease (GVHD) and graft rejection mediated by host and recipient alloreactive T cells, respectively. To address GVHD, we are using Epstein-Barr Virus-specific T cells (EBVST), which are virus specific rather than allo-specific and have not produced GVHD in over 300 allogeneic recipients. To prevent graft rejection, we modified the EBVST with a chimeric antigen receptor (CAR) targeting CD30, an antigen that is upregulated on allo-activated T-cells, which will consequently become targets for CD30.CAR EBVST. Hence, CD30.CAR EBVST can kill both CD30+ lymphoma cells and alloreactive T cells through their CAR, and may be boosted in vivo in EBV+ recipients via their native TCR. We are evaluating this approach in a phase 1 trial (NCT04288726) in patients with CD30+ lymphoma. We generated a bank of 7 CD30.CAR EBVST products by stimulating PBMC from healthy donors with overlapping EBV peptide mixtures followed by retroviral transduction with a 2nd generation, CD28-containing CD30.CAR. We have treated 16 patients (median age 36, range 22–53) with relapsed or refractory HL. Patients had undergone a median of 5 (range 3–7) prior lines of treatment. Escalating doses of 4 × 107 − 8 × 108 (DL1–4) CD30.CAR EBVST were infused after lymphodepletion. The frequency of CD30.CAR EBVST was measured by real time qPCR for the transgene in blood. Changes in the frequency of T-cells responding to EBV or tumor-associated antigens (epitope spreading) were measured by IFNɣ ELISpots. Clinical responses were assessed per Lugano criteria by PET/CT scans performed 4–8 wks post infusion. CD30.CAR EBVST were well tolerated, with no GVHD and only two patients having reversible grade 4 cytopenia. Five patients at DL3–4 had grade 1 cytokine release syndrome (CRS), but all resolved without treatment. Of the 16 patients treated, 6 had partial responses (PR) and 6/13 patients at DL2–4 had complete responses (CR), giving an overall objective response rate (ORR) of 75%. Despite these remarkable responses, qPCR for the CD30.CAR transgene showed near background levels by wk 1 post infusion. Although this could mean that CAR-T are quickly eliminated by alloreactive T-cells, additional infusions from the same donor product into the same patient can be associated with response (Figure 1); an alloreactive response would be anticipated to be amplified after each infusion and preclude additional responses. We are therefore analyzing tumor biopsy samples to determine the presence of CD30.CAR EBVST at tumor sites and characterize their phenotype for functionality. The research was funded by: Leukemia and Lymphoma Society SCOR (Heslop) and Tessa Therapeutics (Rooney/Ramos) through a grant to Baylor College of Medicine. Keywords: cellular therapies, Hodgkin lymphoma Conflicts of interests pertinent to the abstract C. A. Ramos Consultant or advisory role: Novartis, Genentech, CRISPR Therapeutics Research funding: Tessa Therapeutics, Athenex Therapeutics Other remuneration: Royalties: Tessa Therapeutics D. H. Quach Research funding: Tessa Therapeutics P. D. Lulla Research funding: Marker Therapeutics, Allovir R. H. Rouce Consultant or advisory role: Pfizer, Novartis Honoraria: Novartis, Medline Plus Research funding: Tessa Therapeutics B. J. Grilley Consultant or advisory role: Allovir, Marker Therapeutics, Tessa Therapeutics, Lokon Pharma, March Bio and Proxima Clinical Research Stock ownership: Allovir, QBRegulatory LLC N. Lapteva Consultant or advisory role: Tessa Therapeutics Research funding: Tessa Therapeutics M. K. Brenner Employment or leadership position: Founder Member Marker Therapeutics Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Athenex, Turnstone Biologics, Posedia, Tscan, Bluebird Bio, Adaptimmune Therapeutics, Adintus, Onkimure, Triumvira Immunologics, Bellicum Pharmaceuticals, Memgen LLC, Brooklyn Immunotherapeutics, Coya, Astrazeneca Pharmaceuticals Stock ownership: Allovir, Marker Therapeutics, Tessa Therapeutics, Turnstone, Bluebird Bio, Allogene, Walking Fish, AlloVir, Tessa, Tscan Other remuneration: Royalties: Takeda, Bellicum, Marker Therapeutics H. E. Heslop Consultant or advisory role: Gilead Biosciences, Novartis, Tessa Therapeutics, Marker Therapeutics, Kiadis, PACT Pharma, Mesoblast, Ankyra Therapeutics Stock ownership: Allovir, Marker Therapeutics, Fresh Wind Biotechnologies, CoRegen Inc. Research funding: Tessa Therapeutics, Athenex Therapeutics C. M. Rooney Consultant or advisory role: Tessa Therapeutics, Marker Therapeutics, Cell Genix Stock ownership: Allovir, Marker Therapeutics Research funding: Tessa Therapeutics Other remuneration: Royalties: Takeda, Marker, Allovir, Bellicum