Non-Myeloablative Lymphodepleting Conditioning in Patients Undergoing Tumor Infiltrating Lymphocytes (TILs) Therapy; Past, Present, and Future

Introduction

Adoptive cell therapy (ACT) using TILs is being studied in phase 2 and 3 pivotal clinical trials in patients with melanoma and other malignancies. A common feature of ACT using TILs is the administration of non-myeloablative (NMA) conditioning using cyclophosphamide and fludarabine with or without total body irradiation. This NMA lymphodepleting chemotherapy enhances the survival, persistence, and antitumor activity of the infused cells by eliminating regulatory T cells, increasing homeostatic cytokines like IL-7 and IL-15, and eliminating resident T-cells competing for these cytokines. However, an unresolved issue with ACT using TILs is the optimal intensity of NMA chemotherapy that would yield the maximal benefits with the least toxicity. This systematic review focuses on the different NMA regimens used in TILs therapy.

Methods

We systematically searched multiple databases, including Pubmed, Embase, and Cochrane, according to the PRISMA statement on Medline. We used MeSH terms and keywords for TILs, NMA chemotherapy, and cyclophosphamide. We included only prospective articles published in English with available full texts until July 2022. The primary database search yielded 773 articles. We excluded irrelevant, duplicates, and review articles. The final search revealed 16 articles that were explored in detail for years of publication, patients' demographics, disease site, NMA regimen, safety, and efficacy profile.

Results

Early studies (until 2010)

A total of 165 patients (male: 100, female: 65) were enrolled across seven studies from 1991-2010, all with metastatic melanoma except 13 patients with epithelial ovarian cancer. Cy 60mg/kg and Flu 25 mg/m2 were used in two studies (Dudley et al. 2004 and Besser et al. 2009). Cy single agent at a dose of 1 g/m2 was used in two studies (Dillman et al. 1991 and Bears et al. 1992). Cy at a dose of 350 mg/m2 in combination with other agents was used in two studies (Fujita et al. 1995 and Arienti et al. 1993). Median OS was reported as nine months in one study, and 3-yr survival was reported at 100% in another study. The overall response rate (ORR) range was between 24%-51%. The most common toxicities reported were hematologic and febrile neutropenia.

Recent studies (2011-2021)

A total of ten studies met our inclusion criteria, in which 370 patients were included. All with metastatic melanoma except 96 patients with oral cavity SCC. The most common NMA conditioning regimen was Flu 25 mg/m2and Cy 60mg/kg, with only one study using Cy 300mg/m2(Wolf et al. 2020). The Median OS range was between 9.8-38.2 months. Goff et al. (2016) showed that adding TBI was associated with similar efficacy but a higher toxicity rate than no TBI. ORR range was between 29% and 64%. Similar to earlier studies, the most common toxicities were hematologic toxicities and febrile neutropenia.Conclusion

This comprehensive systematic review summarizes NMA chemotherapy regimens used in TILs therapy. The heterogeneity of NMA chemotherapy dosing regimens, TILs technique, patient population, and IL-2 dose precludes conclusions regarding efficacy and safety. Cy 60mg/kg x 2 days and Flu 25 mg/m2 x 5 days is the most common regimen used, especially in recent studies. There is no excitement about adding TBI due to similar efficacy but more toxicity. More recently, Nissani et al. compared the Cy 60 mg/m2 to 30 mg/kg dose, both for two days with 25 mg/kg Flu for five days, and showed similar efficacy results with a better toxicity profile with the lower dose. Therefore, we expect this lower dose to be the most commonly used in future studies. Other than decreasing toxicity, using lower doses of cyclophosphamide can be logistically important due to omitting mesna and allowing outpatient administration of NMA lymphodepleting therapy, which is more convenient for patients.

No relevant conflicts of interest to declare.