Tumor associated antigen specific T cells for Hodgkin Lymphoma

Introduction Hodgkin Lymphoma (HL) Reed Sternberg cells express tumor associated antigens (TAA) that are potential targets for cellular therapies. We recently demonstrated that TAA specific T cells (TAA-T) targeting WT1, PRAME and Survivin were safe and associated with prolonged time to progression in solid tumors [1]. Hence, we evaluated whether TAA-T are safe and elicit anti-tumor effects in patients with relapsed/refractory (rel/ref) HL.

Methods TAA-T products were generated from patients or healthy donors on 2 trials (NCT02203903;NCT03843294). 7 patients (2 allogeneic; 5 autologous) received TAA-T for rel/ref HL or as consolidation after hematopoietic stem cell transplant (HSCT) at dose levels up to 2.0e7/m2 and were monitored for safety and response. Patients could receive Nivolumab as clinically indicated.

Results TAA-T products were predominantly CD3+ T cells (Median 84.9%; range 80.9-99.5%), with CD4+ T cells (Median 10.9%; range 1.74-20%) and CD8+ T cells (Median 69.8%; range 29.3-81.6%)] and NK cells (Median 0.92% (range 0.3-16.8%)). Products manufactured from patients with no PD1 inhibitor exposure (n=2) had significantly higher PD1 expression on CD4+ (p=0.001) and CD8+ T cells (p=0.02) compared to those who were exposed to PD1 inhibitors immediately prior to TAA-T generation (n=4). TAA-T products showed specificity to 1-3 TAAs. Median age of patients was 36 years (range 18-53) and median time to follow-up from TAA-T#1 was 8 months (range 2-32). 6 out of 7 patients completed the 45 days safety monitoring with no DLTs. One allogeneic HSCT recipient had measurable disease pre-infusion and progressed at 6 weeks. He then received Nivolumab off protocol and achieved complete remission (CR) but developed Grade 4 GVHD. The other allogeneic recipient was in CR prior to TAA-T and remained in CR for 2+ yrs. Of the 4 autologous recipients, one patient in CR pre TAA-T remains in CR at 2+ years. 3 with measurable disease pre TAA-T had stable disease at week 6 post TAA-T#1 (duration 1.5-9 months).To evaluate TAA-T persistence, unique T cell receptor clonotypes from a TAA-T cell product were detected in peripheral blood 4 weeks post infusion. Additional data is pending.

Conclusion TAA-T were safe in patients with rel/ref HL including after autologous or allogeneic HSCT. Prolonged continued CRs were observed when TAA-T were given post HSCT. TAA-T can be detected in vivo using TCR sequencing. We are now evaluating whether PD1 exposure plays a role in their long term persistence in vivo.

Study supported by:

1. Leukemia Lymphoma Society’s Translational Research Program

2. Safeway Foundation

3. American Society of Hematology

Conflict of Interest:

Catherine M. Bollard Stock and Other Ownership Interests: Mana Therapeutics, NexImmune, Torque, Cabaletta Bio Consulting or Advisory Role: Torque, NexImmune, Cellectis, Cabaletta Bio Patents, Royalties, Other Intellectual Property: TAA-specific T cells and HIV-specific T cells Patrick J. Hanley Stock and Other Ownership Interests: Mana Therapeutics Honoraria: Dava Oncology Consulting or Advisory Role: Mana Therapeutics, NexImmune Patents, Royalties, Other Intellectual Property: Mana Therapeutics has licensed technology of which I am listed as an inventor from Children’s National, Health System Travel, Accommodations, Expenses: Terumo, Dava Oncology

• References

• 1 Hont AB, Cruz CR, Ulrey R, O’Brien B, Stanojevic M, Datar A, Albihani S, Saunders D, Hanajiri R, Panchapakesan K, Darko S, Banerjee P, Fortiz MF, Hoq F, Lang H, Wang Y, Hanley PJ, Dome JS, Bollard CM, Meany HJ. Immunotherapy of Relapsed and Refractory Solid Tumors With Ex Vivo Expanded Multi-Tumor Associated Antigen Specific Cytotoxic T Lymphocytes: A Phase I Study. J Clin Oncol 2019; 37 (26) : 2349-2359 .