Phase I Dose Esclation of Activated T Cells (ATC) Armed with Anti-CD3 × Anti-CD20 Bispecific Antibody (CD20Bi) after Stem Cell Transplant (SCT) In Non-Hodgkin's Lymphoma (NHL)
Authors: Lum Lawrence G. , Ratanatharathorn Voravit , Thakur Archana , Al-Kadhimi Zaid , Skuba Cassara , Paul Elyse N. , Steele Patricia A. , Ayash Lois , Abidi Muneer H. , Uberti Joseph P. 
Published: October 2019

Abstract 488

Relapse rates after autologous peripheral blood stem cell transplant (SCT) for high risk refractory or relapsed NHL patients (pts) remain unacceptable. Resistance to rituximab is a major limitation to successful treatment in pts with NHL. In preclinical studies, we showed that anti-CD3 activated T cells (ATC) armed with CD20Bi could kill rituximab-resistant CD20+ lymphoma cells (Exp Hemat 33:452). Arming ATC with CD20Bi converts each ATC into a CD20-specific cytotoxic T cell. A phase I trial was done in 15 high risk or refractory NHL pts (ages 54–67) who met eligibility criteria for SCT to determine: 1) whether multiple infusions of armed ATC (aATC) given after SCT are safe (primary endpoint); 2) whether infusions accelerate immune recovery (secondary endpoint); and 3) whether such infusions induce an anti-lymphoma effect (secondary endpoint). T cells were activated with OKT3 and expanded in IL-2 from a leukopheresis product, armed with CD20Bi, and cryopreserved for infusions after SCT. At the time of SCT, there were 6 pts in 1st or 2nd complete remission (CR), 4 pts with primary refractory disease (PRD), 4 pts in partial response, and 1 pt with progressive disease (PD). The first 3 patients received 5 × 109 aATC three times per week for 3 weeks and then once per week for 6 weeks for a total aATC dose of 75 × 109. For logistical reasons, the schedule was revised to 1 infusion/week for 4 weeks with dose levels of 10, 15, and 20 × 109 aATC per infusion for total doses of 40, 60, and 80 × 109 aATC. The median dose of CD34+ cells/kg was 4.0 × 106 (1.04-12.30 × 106) and median total infused dose of aATC was 67 × 109 (8.5-80 × 109). The median viability of ATC product was 92%. The ATC product for 15 patients contained medians of 96.5% CD3+, 67% CD4+, and 48.9% CD8+ cells. A total of 15 pts received aATC and 12 of 15 pts were evaluable for aATC toxicities (received >80% of targeted dose). The table summarizes side effects by the number of episodes by dose level for grade 1–3 scores up to 7 days after infusions using the NCI Immunotherapy Toxicity Scoring system. The median day to engraftment was 14.75 days (11-28) after SCT. Phenotyping of patient peripheral blood lymphocytes (PBL) before and after the 2nd infusion in 2 pts showed that circulating aATC peaked between 8 and 12 hrs at levels between 25 and 10% of PBL. Phenotyping of PBL showed that the mean %CD4 cells and the CD4/CD8 ratio in PBL were in the normal range up to a month after SCT. There was a >4x increase in the mean (± SD) number of IFNγ EliSpots from preSCT (30.5 ± 20.5/106 PBL) to post SCT (125.6 ± 130/106 PBL). These data show that IFNγ EliSpots after stimulation with CD20+ Daudi targets increased over the preSCT values (p < 0.008, paired-Wilcoxon test). The median cytotoxicity directed at K562 targets mediated by NK cells was 8.2, 12.7, and 13.7% at 2 weeks, 1 month, and 3 months, respectively. Serum cytokines/chemokines peaked ∼4 hrs after infusions. There was a >250x increase in IL-2 receptors, >10x increase in IL-2, IL-7, and IL-15, >100x increase in MIP-1β and IP10, and >10x increase in MIP-1α, MIG, and MICP-10. At 90 days after SCT, 9 pts were in CR and 6 pts had PD. The median survival for all patients is 20.9 months, for pts who were transplanted in CR remains undefined, and for those transplanted with PRD is 20.4 months. These findings strongly show that expanding ATC from heavily pretreated NHL pts is feasible, aATC infusions are safe, induce high levels of serum cytokines and chemokines, and may accelerate recovery of helper and cytotoxic T cell functions after SCT. These results will help design future approaches to increase the GVL effect after SCT for CD20+ malignancies.

Table: Grade 1-3 Events (NCI Immunotherapy Toxicity) Dose 5 billion 10 billion 15 billion 20 billion # of Pts 3 3 3 3 # of infusions 15 4 4 4 Fever 3 10 12 12 Chills 2 7 10 8 N/V 0 7 3 4 Hypotension 3 4 1 5 Headache 0 2 2 3 Malaise 1 2 7 11 Diarrhea 0 2 0 0 Hypertension 0 1 0 0 Tachycardia 3 2 5 4 Dyspnea 1 0 0 0 Hypoxia 0 0 0 1

Disclosures:

Lum: Transtarget Inc: Equity Ownership.