Medicines

TIL-based ACT regimes show promise in a range of solid cancers


The combination of adoptive cell therapy (ACT) with tumour infiltrating lymphocytes (TIL) and checkpoint inhibitors (CPI) appear to show promise in heavily pretreated patients with a range of solid cancers.

A Danish study, published in the Journal for Immunotherapy of Cancer, comprised 25 adults with metastatic disease across 10 solid cancer types including colon cancer and melanoma.

Patients received non-myeloablative conditioning chemotherapy with cyclophosphamide and fludarabine phosphate ahead of the infusion of in vitro expanded cells. Patients also received bone marrow stimulation with pegfilgrastim and subcutaneous IL-2 injections.

The study said anti-CTLA antibody ipilimumab was administered >2–6 weeks before tumour removal to optimise in vitro expansion. As well, the anti-PD-1 antibody nivolumab was administered 2 days before and in the weeks after TIL infusion to improve in vivo efficacy.

The phase 1/11 study found in vitro TIL expansion to therapeutic levels was successful in 30 out of 31 patients (97%).

The most severe toxicity was due to the conditioning chemotherapy (neutropenia, thrombocytopenia, anaemia) and IL-2 (fever, fatigue, performance status drop).

“Two patients suffered from grade 4 dyspnea after TIL infusion and one was transferred to the intensive care unit for temporary assisted ventilation.”

The study found five patients had sizeable tumour regressions of 30%–63% including two patients with confirmed partial responses (PRs).

“The PRs consisted of one patient (patient 8) with cholangiocarcinoma (CC) that demonstrated total regression of a smaller lung metastasis and another patient (patient 19) with head-and-neck squamous cell carcinoma (HNSCC) who experienced total regression of several sizeable lung metastases.”

“Both patients eventually suffered from progressive disease.”

The disease control rate was 32% with eight patients experiencing either PR or stable disease (SD) >4.5 months. The median progression-free survival was 89 days and median overall survival was 227 days.

“The patients in the disease control group had a significantly longer OS (p=0.041) than the non-disease control group, with a median survival of 465 days vs 142 days, respectively.”

The investigators said they had demonstrated the safety and feasibility of TIL-based ACT in a wide range of solid cancer types.

“Despite many patients being heavily pretreated with chemotherapy and/or immune therapy, TIL expansion and therapy could be completed for the great majority. Furthermore, we show that the addition of CPIs both before and during TIL infusion with low-dose IL-2 only adds manageable and expected toxicity comparable to CPI monotherapy.”

They noted the number and degree of adverse events from low dose IL-2 were more pronounced than what has been reported with low-dose IL-2 in previous studies in metastatic melanoma.

“Retrospectively, it was evident that IL-2 was not well tolerated in the non-benefit group and was often prematurely discontinued. These patients generally had a very poor survival (median OS of 159 days) indicative of a fragile clinical state,” the study said.

The investigators said it was difficult to distinguish whether the TILs, chemotherapy, CPIs, IL-2, or a combination was the main driver of clinical response.

“However, in vitro antitumour reactivity and clinical efficacy in chemotherapy and CPI-resistant patients, as seen in the patient with HNSCC, is suggestive of a beneficial role of the TILs.”

They concluded that while promising, more work was needed to optimise the clinical efficacy of  TIL-based ACT before it can be considered a viable therapeutic option.

 

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