Studies in immune checkpoint blockade against malignant mesothelioma have delivered disappointing results, leading experts to suggest that the future of mesothelioma treatment rests in combination approaches, including immunotherapies and traditional treatments.
An extensive overview titled “Immunotherapy for malignant mesothelioma: Reality check,” published in the journal Expert Review of Anticancer Therapy, also emphasized that the roles of emerging immune checkpoint receptors need to be explored because they might hold potential for further advances.
The review was provided by researchers from three Australian research institutions: the University of Melbourne, Garvan Institute of Medical Research, and the Olivia Newton-John Cancer Research Institute.
Although early studies of immunotherapy in mesothelioma showed promise for significant treatment improvement, development has been disappointing. Clinical trials have tested cytokines such as IL-2 — a mediator driving immune responses — and tumor vaccines. Trials of so-called CAR T-cells are also underway.
Most work has been done with checkpoint inhibitors. Checkpoint molecules on the surface of immune cells are a critical part of the system for preventing autoimmune or exaggerated immune reactions. When hijacked by a tumor, the system prevents the immune system from turning against the cancer.
Studies show that immunotherapy, particularly immune checkpoint blockers, work best in tumors with plenty of mutations. But mesothelioma is typically not loaded with mutations, which might explain poor trial results.
The checkpoint blocker tremelimumab failed to show any survival benefits in the DETERMINE trial (NCT01843374), composed of 382 patients treated with the drug and 189 participants receiving placebo.
Trials of other checkpoint blockers have been performed or are ongoing, but the review authors noted difficulty in predicting which mesothelioma patients may benefit from such treatment. The lack of knowledge has spurred numerous studies looking for markers that would distinguish patients likely to respond from those unlikely to benefit. The most promising finding is that tumors that express the receptor for PD-L1, called PD-1, are more responsive to treatment.
Across studies of various types of cancer, it was determined that less than 20 percent of patients (in groups where no specific selection was made) respond to a single checkpoint inhibitor.
The low success rates have forced researchers to investigate combination therapies using two checkpoint blockers, or a checkpoint blocker and a cancer vaccine combination.
Because antibodies targeting the checkpoint molecule CTLA-4 have the potential to drive T-cells into the tumor — in turn gearing up the presence of PD-L1 on the tumor — response to PD-1 targeting drugs would potentially increase.
Trials in other cancer types combining the CTLA-4 specific drug Yervoy (ipilimumab) with PD-1-targeting Opdivo (nivolumab) showed that the combination seems to trigger synergistic responses, in which the sum of treatment effect is greater than what can be expected from individual contributions.
The CheckMate 067 study (NCT01844505) showed that the combination gave patients a progression-free survival (PSF) of 11.5 months. In those treated only with Yervoy, PFS was 2.9 months, and in Opdivo alone PFS was 6.9 months.
A different scenario emerged when analyzing results based on the presence or absence of PD-L1 in the tumor. Both the combination and Opdivo gave patients 14 months to live without progression if their tumors expressed PD-L1. In patients whose tumors lacked the factor, combination treatment gave patients 11.2 months PFS, while Opdivo alone only gave patients 5.3 months PFS.
Because nearly 60 percent of mesothelioma tumors lack PD-L1, using other checkpoint inhibitors could be used to trigger response to PD-1 blocking treatment.
In mesothelioma, the Phase 2, open-label NIBIT-MESO-1 trial (NCT02588131) is exploring the combination of tremelimumab and durvalumab to target PD-L1. The combination is also being studied in the ongoing trials (NCT02592551 and NCT02141347).
Because combinations of checkpoint inhibitors are known to increase the risk of side effects, combining a checkpoint blocking drug with a therapeutic cancer vaccine may be a better option because studies show that such combinations are safer. There are no trials investigating such combinations in mesothelioma.
Studies exploring older types of immunotherapy that include interferons or combinations of immunotherapy with traditional chemotherapy or surgical interventions, indicate that the approaches may have a larger chance of success than single immunotherapy drugs.