TIL Therapy LN-145 Shows Promise in Cervical Cancer

Amir A. Jazaeri, MD

The tumor infiltrating lymphocyte (TIL) therapy LN-145 (lifileucel) elicited an objective response rate (ORR) of 44.4% in patients with pretreated advanced cervical cancer, according to findings presented at the 2021 SGO Virtual Annual Meeting on Women’s Cancer.

"These early data with limited follow-up demonstrate feasibility, safety, and a promising objective response rate of 44% for LN-145 TIL immunotherapy in patients with advanced and recurrent cervical cancer who have progressed on prior systemic therapy," lead investigator Amir A. Jazaeri, MD, from the MD Anderson Cancer Center, said during the presentation. "TIL products are highly polyclonal with little commonality across patients, suggesting identifying a common TCR for targeting cervical cancer may be difficult."

LN-145 consists of autologous TILs that are harvested from the site of the tumor using apheresis, with the rationale that these cells can find and kill the tumor cells, Jazaeri noted. The TILs are then expanded ex vivo and administered, once a sufficient number of cells has been reached. Prior to administration, patients received lymphodepleting chemotherapy with cyclophosphamide and fludarabine and following infusion of the TILs up to 6 doses of high-dose IL-2 was administered to support immune expansion and proliferation.

Initial data from the study were from 27 patients with metastatic (52%), recurrent (37%), or persistent (11%) cervical cancer. The median age of patients enrolled was 45 years and the most common baseline ECOG performance status was 1 (63%). Patients primarily had squamous cell carcinoma (44%) and adenocarcinoma histology (44%). The mean number of prior therapies received was 2.4, which included platinum-based chemotherapy for all patients, a taxane for 96% of patients, an anti-VEGF agent for 82% of patients, plus other therapies. Overall, 15% of patients had received an immune checkpoint inhibitor prior to study entry.

The ORR seen with LN-145 consisted of a complete response in 11.1% of patients (n = 3) and a partial response in 33.3% of patients (n = 9). Additionally, 40.7% of patients experienced stable disease, for an overall disease control rate of 85.2%. The median duration of response was not yet reached at the time of the analysis (range, 2.6+ to 9.2+).

The most common treatment emergent adverse events (TEAEs) of any grade occurring in patients following LN-145 were chills (77.8% of patients), anemia (55.6%), diarrhea (51.9%), pyrexia (51.9%), thrombocytopenia (51.9%), neutropenia (40.7%), and vomiting (40.7%). The most common grade 3/4 TEAEs were anemia (55.6%), thrombocytopenia (44.4%), neutropenia (29.6%), febrile neutropenia (29.6%), and leukopenia (22.2%).

"The vast majority of responses exceeded 6 months, and 8 of the 9 partial responses were ongoing at data cutoff," Jazaeri said. "Most of the adverse events occurred in the first weeks after TIL infusion and were related to the expected effects of lymphodepleting chemotherapy and IL-2."

The initial efficacy findings were presented at the 2019 ASCO Annual Meeting and data presented at SGO remained the same. In June 2018, the PD-1 inhibitor pembrolizumab (Keytruda) was approved during the course of the LN-145 study. As a result, 2 cohorts were added to the study to further explore the impact and potential benefits of pembrolizumab on the TIL therapy, Jazaeri said (NCT03108495).

In the first cohort, LN-145 will be administered following 1 to 3 lines of systemic therapy and pembroliuzmab for patients with recurrent, persistent, metastatic cervical cancer. In the second cohort, pembrolizumab will be added to treatment with LN-145 as 1 dose prior to lymphodepletion and for every 3 weeks following the 6 doses of IL-2 for treatment-naïve patients with metastatic cervical cancer. Both cohorts are enrolling 24 patients. Data for these cohorts were not yet available.

Since the initial presentation of efficacy data, subsequent translational studies have explored the in vivo persistence of the TILs. At SGO, Jazaeri presented findings looking at the clonality and reactivity of the TILs and whether it was associated with response in the initial 27 patients. These findings were also presented at the 2020 ESMO Congress.

"T cells are clonal populations that undergo expansion once they recognize their target antigen. Therefore, in a T cell population, diversity or clonality is a measure for how many unique epitopes are recognized by the overall T cell population," Jazaeri said. "Clonality can be determined using next-generation sequencing of the unique complementarity-region of the T cell receptor (TCR) and it is also important to keep in mind that TIL reactivity can be directed at cancer or non-cancer related antigens."

Overall, this evaluation found that LN-145 was highly polyclonal, with approximately 17,000 clonotypes per product. Overall, there was low commonality of the TCR across the 27 patients, with only 6% of TCRs present in more than 1 product and less than 1% of TCRs were found in more than 3 patients products, which suggests the therapy is highly individualized. HPV reactivity did not predict response and long-term TIL persistence was not associated with clinical response.

_{Jazaeri AA, Zsiros E, Amaria RN, et al. Safety & efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. Presented at: SGO 2021 Virtual Annual Meeting on Women’s Cancer; March 19-26, 2021; virtual.}