Tumor-Infiltrating Lymphocyte Therapy Advances Into Melanoma

Omid Hamid, MD, gives his perspective on the use of tumor-infiltrating lymphocyte therapy for patients with melanoma.

Harnessing the power of the immune system with tumor-infiltrating lymphocyte (TIL) therapy has emerged as a promising approach in cancer treatment. TIL therapy involves harvesting T cells that have naturally infiltrated the tumor microenvironment and that recognize tumor-
specific antigens. These TILs are then isolated, expanded ex vivo to generate large numbers, and infused back into the patient following lymphodepletion chemotherapy. The reinfused TILs can then mount a potent antitumor immune response to recognize and attack cancer cells throughout the body. This personalized approach enhances the patient’s own immune system, allowing for a highly targeted and potentially curative treatment strategy. Recently, the FDA’s approval of lifileucel has offered a new therapeutic option for patients with metastatic melanoma. In this article, Omid Hamid, MD, delves into the intricacies of TIL therapy, shedding light on its clinical efficacy, future directions, and potential implications for melanoma management.

Q / Who is the ideal candidate for TIL therapy today?

Hamid / Based on approval of TIL therapy, the ideal candidate is a patient in the second line and beyond who has experienced treatment failure with first-line therapy with a PD-1 backbone.¹ This patient could be of any age, have good cardiac and pulmonary function, and not have any contraindications (eg, ongoing infection, cytopenias).² This could be any patient independent of BRAF status, as BRAF inhibition had failed in patients who were on these trials. This patient could be part of an institution that does TIL therapy, and that is basically it.

Patients with a variety of other solid tumors would be fit for a clinical trial as the horizons of TIL therapy expand.³ There are now first-line trials, such as TILVANCE-301 [NCT05727904], in advanced melanoma.⁴ So, a whole host of patients should be considered for TIL therapy.

Q / Please walk us through a patient’s experience with
TIL treatment.

Hamid / The discussion about where TILs would fit in the patient’s therapeutic paradigm for advanced melanoma is given.² The decision is made to move into a TIL trial. At that point, the patient’s journey goes in multiple directions. The first is an evaluation of the cardiac status, pulmonary function, and baseline laboratory tests. The patient would then be evaluated by a surgical oncologist who has expertise in TIL therapy. Imaging is reviewed for the appropriate place to do a TIL harvest. As our experience has shown, that can be anywhere, whether it is a dermal metastasis, a subcutaneous area, lymph nodes, a visceral area, or other.

The patient undergoes a surgical procedure, and that tumor is harvested and sent out.² A discussion is then had with the manufacturer about when the TILs will be evaluated and ready for infusion, and then that clock starts. The therapeutic team at the treatment center would then schedule a time in the infusion center for lymphodepleting chemotherapy that prepares the patient by decreasing the T cells in the periphery that are not tumor specific. A plan is made for the patient to be hospitalized after the lymphodepleting chemotherapy; the patient is then hospitalized and given the TILs, which have been cryopreserved and shipped back to the therapeutic center.

Those TILs are thawed and infused into the patient. Shortly afterward, the patient enters a monitored area and receives infusions of up to 6 doses ofIL-2.² That is to stimulate those T cells. The patient is then monitored until the blood counts recover until he or she is stable enough to be discharged home. They are discharged home with prophylactic antibiotics and follow-up appointments with their medical oncologist. We tell the patient to stay within the area if an adverse event (AE) occurs, whether that be cytopenias, fever, pain, or another effect. At our institution, we have oncologists on call who are familiar with the AEs of the therapy, and patients can call at any time and be seen.

Q / What safety concerns should be expected during the process of cell therapy?

Hamid / The major toxicities that occur with TIL therapy are associated with the lymphodepleting preparative regimen and the IL-2.⁵ Those are mostly cytopenias (sometimes of long duration) and febrile neutropenia. Toxicities that we have seen with high-dose IL-2 can be related to fluid overload, such as cardiac or pulmonary events and renal insufficiency. Interestingly, the majority of those happen during the 2 weeks of TIL therapy. Once the patient is stable and discharged, there are very few AEs to be seen.

Q / Please discuss efforts to combine TILs with other immunotherapies.

Hamid / It seems that the whole history of TILs has begun now with lifileucel. It is very hard for people who have not been in the field or who are watching the field to understand that there have been combinatorial trials with TILs for many years.⁶ At this point, the main focus is the combination of TILs with anti–PD-1 therapy.³ There has been a phase 1/2 trial looking at a combination in untreated patients in whom we have seen high clinical benefit rates and tolerability.

TILVANCE-301, a randomized phase 3 trial in melanoma that is accruing patients, is looking at TIL therapy plus PD-1 inhibition versus PD-1 inhibition alone in patients with advanced melanoma.⁴ It is moving TIL use earlier and earlier into treatment based on the results of some of the trials we have seen, including the results of 1 study that showed high response rates (48%) with TILs given to patients receiving second-line therapy.⁷ The question is: Should we be seeing this earlier and earlier in our therapeutic regimen?

Additionally, there are data with TIL therapy used in combination with BRAF agents that have been presented before.⁸ As we become more familiar with it, I have no doubt that there will be a push to not only move it earlier into the therapeutic paradigm but also combine it with more tolerable combinations of immunotherapeutics. Once you have a drug that has shown single-agent activity with long-term durability, as this has shown, then the movement into combinations with proven agents is the next logical phase.

Q / Currently, lifileucel is approved in subsequent-line therapy. Could TILs play a role in first-line treatment?

Hamid / Absolutely. We see greater efficacy of TILs as the performance status of the patient is better and they can handle therapy better.5 In the trials of lifileucel, in the initial cohorts 2 and 4, a significant proportion of patients were primary refractory to checkpoint inhibitors. The C-144-01 study [NCT02360579] updates have shown a high response rate (31.4%).⁹ This is in 153 patients, and it is a response rate that is one of the highest—if not the highest—in patients with refractory disease. There is an early time to response (less than 2 months), median time to response, and long durations of response, with ongoing responses of nearly 4.5 years. Looking at patients early with an indication that they are not responding to checkpoint inhibition and then switching them to TILs is where this is going.

Q / How do you see lifileucel fitting into current therapeutic guidelines for melanoma treatment?

Hamid / Lifileucel will definitely be in any therapeutic paradigm with a big asterisk that says that the patients have to be well suited for it. We may exclude patients from receiving TIL therapy due to their cardiorespiratory status, their performance status, or the pace of the growth of their disease.² But the main point to be made with this approval is that we have opened the floodgates for patients to learn more about and be considered for any type of T-cell therapy, whether it be the ImmTACs [immune mobilizing monoclonal T-cell receptors against cancer], like the PRAME bispecific, or tebentafusp therapy.^10,11 These are therapies that redirect T cells into the tumor. Whether it is CAR-T trials or natural killer cell trials that are being looked at in melanoma, that field is now wide open.

Q / What are some of the most significant challenges that must be overcome in TIL therapy to have a greater impact on patients with melanoma?

Hamid / The main challenges for TIL therapy begin with the access to patients. We need to have centers that have the appropriate resources—the physicians, the medical oncologist, the surgical oncologist, the therapeutic center, the beds in the hospital, and the supportive care that is necessary in the wards and in the clinics.² There are about 50 Centers of Excellence set up so far. As physicians who have had a long-term relationship with this therapy, it behooves us to educate our colleagues to understand the need for more centers to provide TIL treatment. Of course, TIL therapy is something that takes time to make. It is usually 3 to 4 weeks to manufacture the TILs, and we are looking to have manufacturing centers that can meet the demand for TILs.

Additionally, we have to clarify what the cost is going to be and where the payers stand with this. With any recently approved therapy, the question is: Will this be reimbursed appropriately, and do we have the right pathways? That is the hesitancy.

Q / How is genetic engineering being used to improve the safety and/or efficacy of TILs?

Hamid / We are CRISPR-ing out certain genes that are deleterious to the immune response. If we can CRISPR out PD-1, we may not need to give TILs with a PD-1 inhibitor.¹² Then we do not need to deal with excess toxicities that occur when we combine immunotherapies or any type of therapy. There is an ongoing trial of the PD-1 CRISPR.¹³

Some groups are looking at whether we can decrease the amount of the preparative chemotherapeutic regimen. Others are looking at the other side. For example, investigators associated with a phase 1 trial are looking at using IL-15 in a different capacity. Instead of IL-2, we may use IL-15 when we believe that the toxicities may be less and the stimulation of regulatory T cells may be less.¹⁴ This could be a more manageable treatment that requires less time in the hospital.

Q / Where do you see the future of adoptive cell therapy heading?

Hamid / The future is bright for adoptive cell therapy. The future will be the realization of this modality as having a true value not only in melanoma but also in other solid tumors.³ This is an extremely important therapeutic in patients with advanced cervical cancer, where we do not have second-line options. The data in an ongoing trial in non–small cell lung cancer are forthcoming, but early experience has shown responses and durability. Let us not forget that the combinations with PD-1 have looked at other solid tumors, including head and neck cancer.

There are responses in breast cancer and colorectal cancer, so a wide range of tumors are being looked at with this modality, including sarcomas.³ We are at the beginning of the marathon with this new modality. We have to train our colleagues to be able to give this therapy and impress upon them every chance we get—at meetings, through print, through video—that this is a modality that should be considered for a multitude of solid tumor indications.

References

1. FDA grants accelerated approval to lifileucel for unresectable or metastatic melanoma. FDA. February 16, 2024. Accessed March 15, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-lifileucel-unresectable-or-metastatic-melanoma
2. Warner AB, Hamid O, Komanduri K, et al. Expert consensus guidelines on management and best practices for tumor-infiltrating lymphocyte cell therapy. J Immunother Cancer. 2024;12(2):e008735. doi:10.1136/jitc-2023-008735
3. Kazemi MH, Sadri M, Najafi A, et al. Tumor-infiltrating lymphocytes for treatment of solid tumors: it takes two to tango? Front Immunol. 2022;13:1018962. doi:10.3389/fimmu.2022.1018962
4. Olson D, Hong Y, Thomas SS, et al. A phase 3 study (TILVANCE-301) to assess the efficacy and safety of lifileucel, an autologous tumor-infiltrating lymphocyte cell therapy, in combination with pembrolizumab compared with pembrolizumab alone in patients with untreated unresectable or metastatic melanoma. J Clin Oncol. 2023;41(suppl 16):TPS9607. doi:10.1200/JCO.2023.41.16_suppl.TPS9607
5. Sarnaik AA, Hamid O, Khushalani NI, et al. Lifileucel, a tumor-infiltrating lymphocyte therapy, in metastatic melanoma. J Clin Oncol. 2021;39(24):2656-2666. doi:10.1200/JCO.21.00612
6. Rosenberg SA, Yannelli JR, Yang JC, et al. Treatment of patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and interleukin 2. J Natl Cancer Inst. 1994;86(15):1159-1166. doi:10.1093/jnci/86.15.1159
7. Rohaan MW, Borch TH, van den Berg JH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. N Engl J Med. 2022;387(23):2113-2125. doi:10.1056/NEJMoa2210233
8. Borch TH, Harbst K, Rana AH, et al. Clinical efficacy of T-cell therapy after short-term BRAF-inhibitor priming in patients with checkpoint inhibitor-resistant metastatic melanoma. J Immunother Cancer. 2021;9(7):e002703. doi:10.1136/jitc-2021-002703
9. Chesney J, Lewis KD, Kluger H, et al. Efficacy and safety of lifileucel, a one-time autologous tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with advanced melanoma after progression on immune checkpoint inhibitors and targeted therapies: pooled analysis of consecutive cohorts of the C-144-01 study. J Immunother Cancer. 2022;10(12):e005755. doi:10.1136/jitc-2022-005755
10. Hamid O, Sato T, Davar D, et al. 728O Results from phase I dose escalation of IMC-F106C, the first PRAME x CD3 ImmTAC bispecific protein in solid tumors. Ann Oncol. 2022;33:S875. doi:10.1016/j.annonc.2022.07.854
11. Hassel JC, Piperno-Neumann S, Rutkowski P, et al. Three-year overall survival with tebentafusp in metastatic uveal melanoma. N Engl J Med. 2023;389(24):2256-2266. doi:10.1056/NEJMoa2304753
12. Chamberlain CA, Bennett EP, Kverneland AH, Svane IM, Donia M, Met Ö. Highly efficient PD-1-targeted CRISPR-Cas9 for tumor-infiltrating lymphocyte-based adoptive T cell therapy. Mol Ther Oncolytics. 2022;24:417-428. doi:10.1016/j.omto.2022.01.004
13. Chesney J, Wise-Draper T, Sarnaik AA, et al. 883TiP A phase I/II open-label study (IOV-GM1-201) of TALEN-mediated PD-1 inactivated autologous tumor-infiltrating lymphocytes (TIL; IOV-4001) in patients with advanced melanoma and NSCLC. Ann Oncol. 2022;33(suppl 7):S952. doi:10.1016/j.annonc.2022.07.1009
14. Phase I, open-label, study of tumor infiltrating lymphocytes engineered with membrane bound IL15 plus acetazolamide in adult patients with metastatic melanoma. ClinicalTrials.gov. Updated October 16, 2023. Accessed March 15, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT05470283

LEARNING OBJECTIVES

Upon successful completion of this activity, you should be better prepared to:

• Describe the challenges and advantages of tumor-infiltrating lymphocyte (TIL) therapy in melanoma.

• Integrate lifileucel into treatment paradigms for patients with melanoma.

RELEASE DATE: April 1, 2024 EXPIRATION DATE: April 1, 2025

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Disclosures (Dr Hamid): Grant/Research Support (paid to institution): Arcus Biosciences, Inc; Aduro Biotech; Akeso, Inc; Amgen; BioAtla, Inc; Bristol Myers Squibb; CytomX Therapeutics, Inc; Exelixis Inc; Genentech; GSK; Immunocore; Idera Pharmaceuticals, Inc; lncyte; Iovance Biotherapeutics, Inc; Merck; Merck Serono; Moderna, Inc; Merck Serono; NextCure, Inc; Novartis; Pfizer Inc; Regeneron Pharmaceuticals, Inc; Seagen Inc; Torque Bio; Zelluna Immunotherapy; Consultant: 10 Biotech; Alkermes; Amgen; Bactonix; BeiGene; BioAtla; Bristol Myers Squibb; Eisai; Genentech; Georgiamune; GigaGen; Grit Bio; GSK; Idera Pharmaceuticals; lmmunocore; lncyte; Instil Bio; Iovance Biotherapeutics; Janssen; KSQ Therapeutics; Merck; Moderna; Novartis; Obsidian Therapeutics; Pfizer Inc; Regeneron; Sanofi; Seagen; Tempus; Vial Health Technology; Zelluna Immunotherapy; Speakers Bureau: Bristol Myers Squibb; Immunocore; Novartis; Pfizer; Inc; Regeneron Pharmaceuticals, Inc; Shareholder: Bactonix.

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