An Update On The Clinical Activity Of Resimmune, a Targeted Therapy Directed To CD3 Receptor, In Patients With Cutaneous T Cell Lymphomas--CTCL

Cutaneous T cell lymphoma—CTCL is a malignancy of skin-tropic T cells. CTCL cells have ubiquitous overexpression of CD3. Although uncommon, CTCL has been estimated to affect 1,500 patients per year in the United States. There are multiple approved systemic therapies for CTCL, but responses are brief lasting months. Allogeneic stem cell transplantation may provide long-term remissions, but is suitable for only rare CTCL patients. Overall, CTCL has a long clinical course with relentless progression over months to years with estimated median survival of 3-5 years for stage IB-IIB patients.

The CD3 targeted agent, Resimmune, was synthesized and prepared for clinical use. It consists of the catalytic and translocation domains of diphtheria toxin fused to two anti-human CD3 Fv fragments. DNA encoding Resimmune protein was integrated into the Pichia pastoris genome, and recombinant protein was produced in Pichia pastoris via the secretory route (Woo, Protein Expr Purif 25, 270, 2002). Protein was purified by anion exchange and size exclusion chromatography. The CD3+ Jurkat cell line incubated with Resimmune yielded an IC₅₀ for protein synthesis inhibition of 0.017pM. The CD3- Vero cell line incubated with Resimmune showed an IC₅₀ >10pM. Mice, rats, and monkeys given total doses of >200mg/kg over four days showed only transient transaminasemia without histopathologic tissue injury or clinical signs or symptoms (Woo, Cancer Immunol Immunother 57, 1225, 2008). In a mouse model with human CD3e transfected lymphocytes, four logs of antigen positive cells were reproducibly depleted from nodes and spleen with 100mg/kg total dose of Resimmune (Thompson, Protein Eng 14, 1035, 2001).

Based on these findings, a phase 1 study was initiated and this report serves to update the results of a single cycle of Resimmune given at 2.5-11.25mg/kg 15 min IV infusion twice daily for 8 doses to 18 CTCL patients. There were 10 females and 8 males with ages 20-81 years. Two patients were naïve to systemic therapies, and all others had failed 1-4 prior treatments including interferon, bexarotene, gemcitabine, vorinostat, chlorambucil, etoposide, pralatrexate, doxil, romidepsin, methotrexate, CHOP, and brentuximab vedotin. None of the Resimmune treated CTCL patients had dose-limiting toxicities. Side effects were mild-moderate and transient with fevers, chills, nausea, transaminasemia, hypoalbuminemia, lymphopenia, reactivation of EBV and CMV, and hypophosphatemia. Toxicities responded to antipyretics, anti-emetics, albumin infusions, rituximab treatment and valgancyclovir. Among measured patients, there was a 3 log decline in normal, circulating T cells by day 5 that recovered by day 14. Because of vascular leak syndrome toxicities in non-CTCL patients, the MTD was defined as 7.5mg/kg x 8 doses. Cmax ranged from 1.9-40.7ng/mL and half-life from 5-66min. Pretreatment anti-DT titers were 0.9-251mg/mL and day 30 post-therapy increased to 5-4059 mg/mL. 17 CTCL patients were evaluable for response. There were six responses for a response rate of 35%. There were four CRs (24% CR rate). Three of the CRs are over 4-years duration. Patients with IB or IIB disease and mSWAT<50 had an overall response rate of 86% and CR rate of 56%. The long time required to convert from a PR to a CR in the absence of any additional therapy beyond the four treatment days suggest an additional anti-tumor mechanism beyond immunotoxin-induced killing such as immunomodulation. Accrual of patients with mSWAT scores of 50 or less is ongoing.