Two Patients with Metastatic Lung Cancer Achieved Complete Responses to TIL Treatment

The Era of Living Drugs Is Beginning

In cancer, immunotherapies are the general name for treatments that do not act directly on cancer cells, but modify and/or motivate the immune system to act on them.

Since 2010, immunotherapies have been central to developments in oncology. Beyond the immune checkpoint modulators approved so far and used in nearly 20 cancer types, the new area of immunotherapy is cellular therapies. Living drug is another name for these treatments, whose basic principle is to modify particular immune cells directly so they find and destroy cancer, rather than giving patients molecules that trigger immunity against cancer. One type of cellular treatment is tumor-infiltrating lymphocyte (Tumor Infiltrating Lymphocytes= TIL) therapy.

A malignant tumor does not consist only of cancer cells. Alongside them, the tumor also contains connective/supporting tissue cells, various immune cells, fat cells and blood vessel cells; this environment is called the tumor microenvironment. One cell type that can be found inside a tumor is tumor-infiltrating lymphocytes. However, TIL cells are not present at the same density in every tumor. Pathology reports may highlight whether TILs are present.

Clinical Trial of TIL Treatment

In a phase-1 clinical trial, adoptive cell therapy using tumor-infiltrating lymphocytes (TILs) was fully administered to 16 patients with metastatic non-small cell lung cancer and led to complete, long-lasting responses in 2 of them.

Two complete responses continuing after 1.5 years are very impressive and encouraging. This study enrolled patients resistant to standard immunotherapy of the immune checkpoint inhibitor type with metastatic lung cancer. This is a patient group for whom we do not fully know how to provide treatment today.

Study Details

The study, on August 12, in Nature, was published. TIL therapy, a form of immunotherapy, had been studied extensively in melanoma, but this is the first TIL clinical trial in metastatic non-small cell lung cancer. The single-arm, open-ended phase 1 trial included 20 patients whose TILs had been harvested, of whom 16 eventually received their TILs back. Participants' mean age was 54, and all patients had metastatic small cell lung cancer and disease progression after nivolumab monotherapy.

TILs cultured from a patient's own tumor are produced by ex vivo expansion from tumors cultured with interleukin-2. With this method, researchers can produce billions of active T lymphocytes and give them back to a patient. The full treatment regimen included cyclophosphamide and fludarabine lymphodepletion, TIL infusion and IL-2, followed by maintenance nivolumab.

Infusion of TILs combined with lymphodepletion and IL-2 has manageable side effects and mediates tumor regression in several patients, including complete responses.

Promising Results

Of 13 evaluable patients, 3 had confirmed responses and 11 had a reduction in tumor burden. Two patients achieved complete responses continuing 1.5 years after TIL treatment. A durable complete response occurred in a PD-L1-negative never-smoker with low tumor mutational burden and resistance to nivolumab.

This result is especially promising for a large subset of never-smokers, in whom immune checkpoint inhibitors have limited effect. This complete response was observed in a patient in whom we would not expect an immunotherapy response. Low tumor mutational burden, negative PDL-1 and never having smoked are three factors indicating a kind of resistance to immunotherapy; despite this, a complete response was achieved with this particular treatment. This is fascinating.

In analyses related to the research, after TIL treatment, multiple cancer mutation-recognizing T cells were detected, and this was enhanced in patients responding to treatment. The researchers say these early data show that TILs may mediate effective responses in tumor subtypes not susceptible to conventional "immune checkpoint and targeted therapy". Treatment with TILs may therefore extend the scope and impact of immunotherapy to patients more broadly.

Questions Still Waiting to Be Resolved

This study is very promising in some respects, but in others more limited than hoped. What biological / genetic characteristics of patients with complete responses are we unaware of? Something is happening here, and there are things that can be done to improve it, which undoubtedly will be done; I think this is wonderful evidence.

Key problems going forward are how TIL cells are selected and produced. This will be critical to improving living drug use. There is now a wealth of data saying that T cells recognizing cancer mutations can be effective in solid (organ) tumors. Sustaining this response remains a major obstacle to obtaining the benefits we want. Ensuring a sufficiently broad response will also require a way to produce a large, polyspecific cell population that can persist for a long time, particularly where most mutations are merely pessenger (passenger) mutations rather than driver oncogenes.