Oncology Overview: Investigational Autologous TIL Immunotherapy LN-145 for Cervical Cancer

Studies suggest novel immunotherapy may have efficacy as monotherapy and in combination with an anti-PD-1 immune checkpoint inhibitor.

Response rates to available second-line treatments for cervical cancer are poor, estimated to be between 4% and 14 %.1 Adaptive cell transfer therapy with tumor-infiltrating lymphocytes (TILs) may be emerging as a potential treatment for these patients.

The FDA granted the investigational autologous TIL immunotherapy LN-145 (Iovance Biotherapeutics) Breakthrough Therapy designation for the treatment of recurrent, metastatic, or persistent cervical cancer.2 Studies suggest it may have efficacy as monotherapy and in combination with an anti-programmed cell death protein-1 (PD-1) immune checkpoint inhibitor.1,3

LN-145 is composed of tumor-resident T cells that a laboratory isolates from a resected sample of a patient’s tumor and selectively expands ex vivo using a complex 22-day proprietary process in a central facility. The facility cryopreserves the final infusion product, which is unique to each patient, and ships it back to the treatment site for reinfusion into the patient.

Patients receive a single week of non-myeloablative, lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide the week preceding the TIL infusion. They receive up to 6 doses of interleukin-2 following the TIL infusion to promote TIL activation and growth.4,5

The FDA granted LN-145 Breakthrough Therapy designation in May 2019 based on preliminary findings of the phase 2, multicenter, open label, interventional study C-145-04/innovaTIL-04 (NCT03108495).2 This study includes adult patients 18 to 70 years of age (or older with special approval) with recurrent, metastatic, or persistent cervical cancer with disease progression on or after 1-3 prior lines of systemic therapy.

The trial excluded patients with prior exposure to an immune checkpoint inhibitor. The researchers presented preliminary data at the 2019 American Society of Clinical Oncology annual meeting.

At that time, 27 previously treated patients had received LN-145. Investigators reported an observed objective response rate (ORR) of 44%, which included 1 complete response (CR), 9 partial responses (PR), and 2 unconfirmed partial responses (uPR).

In total, 89% of responders exhibited durable responses at a median follow-up of 3.5 months. On average, patients had received 2.6 prior lines of platinum-based chemotherapy, and most had received prior radiotherapy and/or anti-VEGF therapy. Treatment-emergent adverse events (TEAEs) were generally consistent with those of non-myeloablative lymphodepleting chemotherapy and interleukin-2.1

The study has since expanded to include patients previously treated with an immune checkpoint inhibitor (cohort 2), and patients who were previously untreated with any therapy beyond chemoradiation or surgery (cohort 3). Patients in cohort 3 receive LN-145 in addition to the immune checkpoint inhibitor pembrolizumab.

The researchers reported an ORR of 57.1% (1 CR, 6 PR, 2 uPR) with this combination at the November 2021 Society for Immunotherapy of Cancer annual meeting. The researchers identified durable responses in 71.4% of responders at the median follow-up of 7.6 months.

Most TEAEs occurred prior to or within 2 weeks of the TIL infusion and were consistent with those of non-myeloablative lymphodepleting chemotherapy, interleukin 2, and pembrolizumab. Most patients had a combined positive score (CPS) of at least 1%.3

LN-145 is additionally being studied for treatment of other malignancies including melanoma, non-small cell lung cancer, squamous cell carcinoma of the head and neck, triple-negative breast cancer, ovarian cancer, anaplastic thyroid cancer, osteosarcoma, and soft tissue sarcomas.6

Mechanism of Action

LN-145 uses autologous T cells to fight malignancy. In contrast to chimeric antigen receptor (CAR) T-cell therapy, LN-145 is not produced via genetic modification of patients’ T cells.

Rather, the laboratory isolates the endogenous, polyclonal population of tumor-resident T cells, and activates and expands them for reinfusion into the patient. Ex vivo TIL expansion involves selective T cell enrichment that excludes regulatory T cells, resulting in a TIL product composed primarily of non-suppressive CD4+ and CD8+ T cells.4,5

Dosage

The number of T cells delivered to the patient may be highly variable. The average number of cells delivered to cohort 1 of NCT03108495 was 28 x 109. Prior to LN-145 infusion (day 0), patients receive preparatory chemotherapy consisting of cyclophosphamide 60 mg/kg/day on days -7 to -6 (with prophylactic mesna) and fludarabine 25 mg/m2/day on days -5 to -1.

Following LN-145 infusion, interleukin-2 600,000 international units/kg is administered every 8-12 hours for up to 6 doses (beginning 3-24 hour after LN-145 infusion). When used, prescribers start pembrolizumab before preparatory chemotherapy and continue it for up to 24 months.1,2

AEs

TEAEs are reported to be consistent with those of fludarabine, cyclophosphamide, IL-2, and pembrolizumab. TEAEs that occurred in greater than 30% of patients in cohort 3 (NCT03108495) included chills (93%), nausea (86%), vomiting (79%), pyrexia (64%), hypotension (64%), anemia (64%), alopecia (64%), constipation (64%), dyspnea (57%), headache (57%), decreased appetite (50%), thrombocytopenia (36%), and febrile neutropenia (36%).3

Warnings and Precautions

LN-145 has only been used in small groups of subjects and long-term follow-up data are not available. Known risks of treatment with LN-145 are those inherent to the use of lymphodepleting chemotherapy and interleukin-2 (+/-pembrolizumab).

Pregnancy and Lactation

LN-145 has not been studied in pregnant or breastfeeding women. Inclusion criteria for NCT03108495 require participants to avoid pregnancy for the study duration and for 1 year following completion.3

About the Author

Allison Rhoads, PharmD, is a clinical pharmacist at an outpatient oncology center in Tallahassee, Florida.

References

1. Jazaeri AA, Zsiros E, Amaria RN, et al. Safety and efficacy of adoptive cell transfer using autologous tumor infiltrating lymphocytes (LN-145) for treatment of recurrent, metastatic, or persistent cervical carcinoma. J Clinl Oncol. 2019;37(15_suppl):2538. doi: 10.1200/jco.2019.37.15_suppl.2538

2. Iovance Biotherapeutics Announces Breakthrough Therapy Designation for LN-145 for Treatment of Advanced Cervical Cancer Patients Who Have Progressed on or After Chemotherapy. ir.iovance.com. May 2019. Accessed June 27,2022. https://ir.iovance.com/news-releases/news-release-details/iovance-biotherapeutics-announces-breakthrough-therapy?ID=2399491&c=254507&p=irol-newsArticle.

3. O’Malley D. Phase 2 Efficacy and Safety of Autologous Tumor-Infiltrating Lymphocyte (TIL) Cell Therapy in Combination with Pembrolizumab in Immune Checkpoint Inhibitor-Naïve Patients with Advanced Cancers. Presented at: The Society For immunotherapy of Cancer 36th Annual Meeting; November 2021; Washington, D.C. https://www.iovance.com/uploads/Iovance_SITC-2021_Phase-2-Efficacy-and-Safety-of-Autologous-Tumor-Infiltrating-Lymphocyte.pdf

4. Study of LN-145, Autologous Tumor Infiltrating Lymphocytes in the Treatment of Patients with Cervical Carcinoma. ClinicalTrials.gov identifier: NCT03108495. Updated June 9, 2021. Accessed June 27, 2022. https://clinicaltrials.gov/ct2/show/NCT03108495

5. Simpson-Abelson MR, Cedano-Hilton, Angel, D’Arigo K, Fardis M, Chartier C. Iovance Generation-2 Tumor-Infiltrating Lymphocyte (TIL) Product is Reinvigorated During the Manufacturing Process. Poster presented at: ESMO Virtual Congress 2020; September 2020. Accessed June 27,2022. https://www.iovance.com/uploads/IovanceBio-ESMO_Poster_1_2020.pdf

6. National Cancer Institute. Clinical Trials Using Autologous Tumor Infiltrating Lymphocytes LN-145. Accessed July 2, 2022. https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/autologous-tumor-infiltrating-lymphocytes-ln-145