Background Patients with relapsed or refractory Wilms tumor (WT) have poor prognoses with limited treatment options.1–3 Immunotherapy offers a promising alternative for targeted therapy but has been limited by immune evasion tactics.4–6 Adoptive cell therapy with patient-derived tumor-associated antigen-specific T cells (TAA-T) targeting 3 antigens (WT1, PRAME, and survivin) has the potential to overcome antigen loss. The objective of this phase I clinical trial is to determine the safety of administering TAA-T to patients with high-risk, relapsed/refractory solid tumors. Secondary objectives include determination of clinical efficacy and immunobiology following infusion.
Methods T cells expanded from patient peripheral blood are stimulated weekly with antigen presenting cells expressing an overlapping peptide library spanning the tumor antigens WT1, PRAME, and survivin. Following release testing, patients are infused with TAA-T on a dose escalation study, ranging from a dose of 1 x 107/m2 (dose level 1) to 4 x 107/m2 (dose level 3). Clinical and immunobiological studies performed post-infusion monitor for adverse effects and assess immune and disease responses.
Results Therapy with TAA-T was shown to be safe and well-tolerated in patients with high-risk solid tumors on this dose-escalation study.7 A total of 18 patients have been infused, with WT as the predominant diagnosis, accounting for 10 patients. We elucidated a dose-response relationship, with a prolonged median time to progression for patients treated on dose level 3 (recommended dose level [RDL]) compared to those on dose level 1 and 2 combined (5.2 vs 2.8 months, respectively) (figure 1). Patients demonstrated prolonged progression-free survival (PFS) compared to therapy received just prior to TAA-T (figure 2). Best response observed was stable disease. A majority of patients demonstrated improved anti-tumor immunity as evidenced by antigen spreading (figure 3).
Conclusions In long-term follow up, the 1-year progression-free survival (PFS) remains improved for patients treated at the recommended dose level compared to the PFS observed with therapy received immediately prior to TAA-T (29% vs 15%, respectively). Three patients are long-term (28–38 months) survivors without disease progression or further therapy. This unique immunotherapeutic has been well-tolerated without life-threatening cytokine release syndrome. To enhance TAA-T activity further in vivo, we will evaluate the safety of prescribed lymphodepletion prior to TAA-T infusion and assess anti-tumor immunity. We expect that lymphodepletion will enhance T cell persistence and expansion and recruit endogenous immune response with altered kinetics.
Ethics Approval The study was approved by the Children’s National Hospital Institutional Review Board, approval number NCT02789228.
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