Comprehensive phase II trial with Tumor Infiltrating Lymphocytes: Long term safety and activity, prognostic factors to response and impact of reduced preconditioning

Michal Besser ^1,2 Orit Itzhaki ¹ Guy Ben Betzalel ¹ Douglas Zippel ⁴ Dragoslav Zikich ¹ Adva Kubi ¹ Karin Brezinger ¹ Abraham Nissani ¹ Michal Levi ¹ Li-At Zeltzer ¹ Alon Ben-Nun ⁶ Avichai Shimoni ⁵ Arnon Nagler ⁵ Gal Markel ^1,2 Ronnie Shapira-Frommer ³ Jacob Schachter ¹

¹Ella Lemelbaum Institute for Immuno Oncology, Sheba Medical Center, Israel
²Department of Clinical Microbiology and Immunology, Tel Aviv University, Israel
³Oncology Division, Sheba Medical Center, Israel, Israel
⁴Department of Surgical Oncology, Sheba Medical Center, Israel
⁵Department of Bone Marrow Transplantation, Sheba Medical Center, Israel
⁶Department of Thoracic Surgery, Sheba Medical Center, Israel

Adoptive Cell Transfer (ACT) mediates objective responses in 30-50% of metastatic melanoma patients. T cells are typically administered following non-myeloablative (NMA) lymphodepleting with cyclophosphamide and fludarabine (Cy/Flu). Here we report the long-term clinical results, intent-to treat analysis, predictors of response and safety outcomes in 196 enrolled patients. Due to cyclophosphamide-induced toxicity, a reduced preconditioning regimen was evaluated in a subgroup of patients.

Experimental Design:

196 refractory melanoma patients were enrolled, of which 116 were treated with Tumor Infiltrating Lymphocytes (TIL) following NMA with Cy/Flu (n=107) or 200 cGy total body irradiation (TBI) and fludarabine (n=9).

Results:

The objective response (OR) rate in the Cy/Flu cohort was 28%. Predictors to response included, performance status, LDH levels, time of TIL in culture and CD8 frequency in the drug product. The absolute lymphocyte count one and two weeks after TIL infusion was the most predictive parameter of response. By study end, OR patients did not reach the median overall survival (OS) and had a median progression-free survival (PFS) of 15.43 months, as compared to non-responders with 6.61 months OS of and 2.47 months PFS. By 6 years, 50% of OR patients OR were alive and 43% had no documented progression. Substitution of cyclophosphamide by 200 cGy TBI, reduced the toxicity of the treatment, but did not yield clinical effectiveness.

Conclusion:

TIL administration following Cy/Flu conditioning can yield durable objective responses, even as salvage therapy in highly advanced metastatic melanoma patients. Alternatives for a reduced NMA should be further evaluated.