Studies suggest that new immunotherapy may be effective as monotherapy and in combination with an anti-PD-1 immune checkpoint inhibitor.
The response to available second-line treatments for cervical cancer is low, estimated between 4% and 14%.1 Adaptive cell transfer therapy with tumor-infiltrating lymphocytes (TILs) may emerge as a potential treatment for these patients.
The FDA granted the autologous TIL immunotherapy for study 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-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 proprietary 22-day process in a central facility. The facility stores the final infusion product, which is unique to each patient, and returns it to the treatment site for reinfusion into the patient.
Patients will receive a single week of non-myeloablative lymphodeplete chemotherapy consisting of fludarabine and cyclophosphamide in the week prior to TIL infusion. They receive up to 6 doses of interleukin-2 after the TIL infusion to promote TIL activation and growth.4.5
The FDA granted the designation LN-145 Breakthrough Therapy in May 2019 based on preliminary findings from the Phase 2, multicenter, open label, interventional study C-145-04/innovaTIL-04 (NCT03108495).2 This study includes adult patients aged 18 to 70 years (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 study excluded patients who had previously been exposed to an immune checkpoint inhibitor. The researchers presented preliminary data at the American Society of Clinical Oncology annual meeting in 2019.
At that time, 27 previously treated patients had received LN-145. Researchers reported an observed objective response (ORR) of 44%, including 1 complete response (CR), 9 partial responses (PR), and 2 unconfirmed partial responses (uPR).
Overall, 89% of respondents showed a sustainable response after 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 similar to those of non-myeloablative lymph depletion chemotherapy and interleukin-2.1
The study has since been expanded to include patients previously treated with an immune checkpoint inhibitor (cohort 2), and patients not previously treated with any therapy other than chemoradiation or surgery (cohort 3). Patients in cohort 3 will 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 annual meeting of the Society for Immunotherapy of Cancer in November 2021. The researchers identified a sustained response in 71.4% of the respondents after 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 non-myeloablative lymphodepletion chemotherapy, interleukin 2, and pembrolizumab. Most patients had a combined positive score (CPS) of at least 1%.3
LN-145 is additionally being investigated 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 sarcoma.6
Mechanism of action
LN-145 uses autologous T cells to fight malignancies. Unlike chimeric antigen receptor (CAR) T cell therapy, LN-145 is not produced via genetic modification of patients’ T cells.
Instead, the lab isolates the endogenous, polyclonal population of tumor-resident T cells, 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 consisting mainly of non-suppressant CD4 + and CD8 + T cells.4.5
Dosage
The number of T cells delivered to the patient can be highly variable. The mean number of cells delivered to cohort 1 of NCT03108495 was 28 × 109. Prior to the 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 administered 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 for up to 24 months.1.2
AEs
TEAEs have been reported to be consistent with those of fludarabine, cyclophosphamide, IL-2 and pembrolizumab. TEAEs occurring in greater than 30% of patients in Cohort 3 (NCT03108495) included chills (93%), nausea (86%), vomiting (79%), fever (64%), hypotension (64%), anemia (64%), alopecia (64%), constipation (64%), dyspnoea (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 no long-term follow-up data is available. Known risks of LN-145 treatment are those inherent in the use of chemotherapy for lymphatic breakdown and interleukin-2 (+/-pembrolizumab).
Pregnancy and breastfeeding
LN-145 has not been studied in pregnant or breast-feeding women. Inclusion criteria for NCT03108495 require participants to avoid pregnancy during the study duration 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 advanced cervical cancer patients who have progressed on or after chemotherapy. i.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-naive patients with advanced cancers. Presented at: The Society for Immunotherapy of Cancer 36th Annual Meeting; Nov 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 cancer. 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 revived 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 studies with 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