Cellular TIL Therapy Outperformed Conventional Immunotherapy in Melanoma

Cancer immunotherapy is the general term for treatments that do not act directly on cancer cells but modify the immune system so that it acts against them.

Since 2010, immunotherapy has been central to advances in oncology. There are many types of immunotherapy , but almost all approved in the past 10 years are antibody-based drugs called immune checkpoint inhibitors . A promising new area of immunotherapy is cellular therapy. Living drugs , as these therapies are also called, do not primarily involve giving molecules that stimulate immunity against cancer. Instead, specific immune cells are modified directly to find and destroy cancer. One type is tumor-infiltrating lymphocyte (Tumor Infiltrating Lymphocytes = TIL) therapy.

A tumor is not made up only of cancer cells. It also contains connective/supporting tissue cells, various immune cells, fat cells and blood vessel cells. This environment is called the tumor microenvironment . Tumor-infiltrating lymphocytes are one type of cell found within tumors, but TIL density differs among tumors. Pathology reports may note whether TILs are present.

Current Progress and Unmet Needs in Melanoma Treatment

Malignant melanoma, or simply melanoma, is an aggressive cancer accounting for approximately 5% of skin cancers. Today, disease-specific 5-year survival for very early melanoma is 99%, and for locally advanced disease it exceeds 70%. Advanced melanoma, however, remains highly aggressive. Before 2010, its 5-year survival was below 5%; today, checkpoint inhibitors and targeted drugs have brought it close to 40%. Yet approximately half of patients treated with these drugs will not achieve lasting benefit, creating a major need for new options.

TIL Therapy Was More Effective Than Immune Checkpoint Inhibitors

CAR T-cell and other cellular therapies have already transformed blood cancer outcomes, but approval in solid (organ-based) tumors has proved harder. Now, in the first multicenter randomized trial comparing TIL therapy with immune checkpoint inhibitors, which we consider conventional immunotherapy, TIL therapy produced superior results in advanced melanoma.

The trial’s cellular treatment consists of lymphocytes developed specifically for each patient, much like chimeric antigen receptor T-cell (CAR T-cell) therapy for blood cancers and lymphoma. However, CAR T cells are made from circulating blood cells, whereas tumor-infiltrating T cells for TIL therapy are isolated from tumor tissue that must be removed through procedures such as surgery.

The Study Presented at ESMO Congress 2022

Presented at ESMO 2022, this phase 3 trial included 168 patients with unresectable stage 3C-4 melanoma. Compared with standard ipilimumab (Yervoy) immunotherapy, TIL-treated patients achieved significantly improved progression-free survival (PFS, the time treatment keeps disease controlled) .

Median PFS more than doubled with TILs to 7.2 months, compared with 3.1 months on ipilimumab (hazard ratio [HR], 0.50; P < 0.001), representing a 50% reduction in progression risk.

Lead author and research group leader at the Netherlands Cancer Institute in Amsterdam, professor of translational immunotherapy in cancer, Dr. John Haanen, said, “We believe TIL could potentially be a new treatment option for patients with advanced melanoma.”

These results could accelerate TIL research in other cancers, potentially benefiting many other solid tumors and expanding patients’ treatment options.

Although immunotherapy can deliver impressive long-term responses, many patients do not have durable responses to checkpoint inhibitors. TIL therapy has demonstrated efficacy in melanoma, but until now no phase III trial had compared it with standard immunotherapy.

These results are consistent with earlier studies showing approximately 50% overall response and an impressive 20% complete response rate with TILs. TIL treatments have been used in melanoma for approximately 20 years but have not yet been approved by a leading authority. Suitable biomarkers identifying patients most likely to benefit are still urgently needed.

Superior to Conventional Immunotherapy

Haanen and colleagues randomized 168 patients to TILs or ipilimumab (3 mg/kg every 3 weeks, up to 4 doses). Patients were stratified by BRAF V600 mutation status and previous treatment. Most (86%) were resistant to anti-PD-1 immunotherapy.

Patients in the TIL group required removal of a tumor 2-3 cm in diameter to isolate T cells. Before the cultured TILs were returned intravenously to the patients from whom they originated, patients received non-high-dose, immune-space-making chemotherapy with cyclophosphamide plus fludarabine, followed by high-dose interleukin-2.

The primary endpoint was progression-free survival; secondary endpoints included response rates, overall survival and safety.

• At a mean follow-up of 33 months, TIL therapy significantly improved progression-free survival compared with ipilimumab.
• The overall response rate was higher with TILs: 49% versus 21% with ipilimumab. Complete responses also favored TILs, at 20% versus 7%, respectively.
• Median overall survival was 25.8 months with TILs and 18.9 months with ipilimumab (HR, 0.83; P  = 0.39).
• Grade 3 or higher treatment-related adverse events occurred in all TIL recipients and 57% of ipilimumab patients. Haanen said these were manageable and mostly resolved before hospital discharge.

Haanen said, “There were no new safety concerns with TILs”, adding, “These adverse events are driven by the chemotherapy and interleukin-2 that form part of the TIL regimen. Quality of life was higher in TIL-treated patients.”

Ultra-Personalized

In some respects, TIL therapy is ultra-personalized: immune cells are collected from the patient’s tumor, expanded outside the body and then returned to the patient. This trial, randomizing patients between TILs and the CTLA-4 inhibitor ipilimumab, showed impressive benefits in progression-free survival and overall response rate. It will help develop TIL therapy as a viable strategy for some patients.

Conclusion

A new treatment option appears to be emerging for patients who develop resistance after conventional immunotherapy or are resistant from the outset.

However, the study’s main limitation is that ipilimumab is no longer standard treatment for advanced melanoma: the comparison was against an older standard, rather than today’s best initial treatment;

• ipilimumab plus nivolumab appears preferable for patients without a BRAF mutation, while
• for BRAF-mutated patients it appears to be the triplet of atezolizumab with cobimetinib and vemurafenib.

The key question is therefore when TIL therapy should enter treatment for advanced melanoma. Introducing it before resistance develops to other therapies, while the initial treatment response continues, to support a more durable response is an option that should certainly be tested.