Experimental Autologous LN-145 TIL Immunotherapy for Cervical Cancer

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Studies suggest that a new immunotherapy may be effective as monotherapy and in combination with an anti-PD-1 immune checkpoint inhibitor.

Response rates to second-line treatments available for cervical cancer are low, estimated at between 4% and 14%.1 Adaptive cell transfer therapy with tumor-infiltrating lymphocytes (TIL) could become a potential treatment for these patients.

The FDA has granted experimental autologous TIL immunotherapy LN-145 (Iovance Biotherapeutics) Breakthrough Therapy Designation for the treatment of recurrent, metastatic, or persistent cervical cancer.2 Studies suggest that it may be effective as monotherapy and in combination with an anti-protein programmed cell death-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 grows ex vivo using a complex proprietary process of 22 days in a central facility. The facility cryopreserves the final infusion product, which is unique to each patient, and returns it to the treatment site for reinfusion into the patient.

Patients receive a single week of nonmyeloablative, lymphodepleting chemotherapy consisting of fludarabine and cyclophosphamide the week before the TIL infusion. They receive up to 6 doses of interleukin-2 after TIL infusion to promote TIL activation and growth.4.5

The FDA granted Breakthrough Therapy Designation to LN-145 in May 2019 based on preliminary results from 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 during or after 1 to 3 prior lines of systemic treatment.

The trial excluded patients who had previously been exposed to an immune checkpoint inhibitor. The researchers presented preliminary data at the 2019 annual meeting of the American Society of Clinical Oncology.

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).

A total of 89% of responders showed durable responses at a median follow-up of 3.5 months. On average, the patients had already received 2.6 lines of platinum-based chemotherapy, and most had already received radiotherapy and/or anti-VEGF treatment. Treatment-emergent adverse events (TEAEs) were generally consistent with those of lymphodepleting nonmyeloablative 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 had previously received no treatment other than chemoradiotherapy or surgery (cohort 3). Cohort 3 patients receive LN-145 in addition to pembrolizumab, an immune checkpoint inhibitor.

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

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

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

Action mechanism

LN-145 uses autologous T cells to fight malignancy. Unlike chimeric antigen receptor (CAR) T cell therapy, LN-145 is not produced by genetically modifying patient T cells.

Instead, the lab isolates the endogenous polyclonal population of tumor-resident T cells, activates them, and expands them for delivery back into the patient. Expansion of TIL ex vivo involves selective T cell enrichment that excludes regulatory T cells, resulting in a TIL product composed primarily of nonsuppressive CD4+ and CD8+ T cells.4.5

Dosage

The number of T lymphocytes delivered to the patient can be very variable. The average number of cells delivered to NCT03108495 Cohort 1 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.

After LN-145 infusion, interleukin-2,600,000 international units/kg is given every 8-12 hours for up to 6 doses (starting 3-24 hours after LN-145 infusion). When used, prescribers start pembrolizumab before preparatory chemotherapy and continue it for up to 24 months.1.2

IS

The TEAEs would be compatible with those of fludarabine, cyclophosphamide, IL-2 and pembrolizumab. TEAEs that occurred in more 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 is not available. The known risks of LN-145 treatment are those inherent in the use of lymphodepleting chemotherapy and interleukin-2 (+/-pembrolizumab).

Pregnancy and breast feeding

LN-145 has not been studied in pregnant or breastfeeding women. Inclusion criteria for NCT03108495 require participants to avoid pregnancy for the duration of the study and for 1 year after 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 the 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 the treatment of patients with advanced cervical cancer who have progressed during 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. Efficacy and safety of phase 2 autologous tumor-infiltrating lymphocyte (TIL) cell therapy in combination with pembrolizumab in immune checkpoint inhibitor naïve patients with advanced cancers. Presented at: 36th Annual Meeting of the Society for Cancer Immunotherapy; November 2021; Washington, DC 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 ID: 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 invigorated 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 LN-145 autologous tumor-infiltrating lymphocytes. Accessed July 2, 2022. https://www.cancer.gov/about-cancer/treatment/clinical-trials/intervention/autologous-tumor-infiltrating-lymphocytes-ln-145

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