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The importance for immunoregulation for long term cancer control

20th December 2022

In this review, Dr Fusi and Prof Dalgliesh have summarised the new clinical findings with respect to melanoma and outlined the most likely future challenges with the new treatment in terms of toxicity and disease control.

Treatment for patients with advanced melanoma has dramatically improved in the past 10 years. Immunotherapy has become the treatment of choice for the majority of the patients with melanoma, non-small cell lung cancer and renal cell carcinoma. Of all cancer types, melanoma has been the most investigated. More immunotherapy drugs are indeed approved for melanoma than for any other type of cancer, and more are in development. Melanoma has always shown higher responsiveness to immunotherapeutic approaches compare to the other solid tumours.

The anti-PD-1 antibodies, pembrolizumab and nivolumab either as single agent or in combination with the anti-CTLA-4 antibody ipilimumab have shown to significantly improve the outcomes in terms of progression-free survival and overall survival of the patients with metastatic melanoma. Anti-PD1 antibodies have shown a response rate of about 40% in metastatic melanoma when used as single agents and of 60% when used in combination with anti-CTLA-4 antibodies. More recently pembrolizumab and nivolumab used as single agent have also shown to reduce the risk of relapse for patients with completely resected stage III melanoma in the adjuvant setting (completely resected loco-regional disease). Checkpoint inhibitors have also received approval for the treatment of patients with non-small-cell lung cancer and metastatic renal cell carcinoma, with impressive clinical activity and durable responses in some patients.

Single agent check point blockades are generally well tolerated with severe side effects occurring in less than 15% of the patients whereas combination of ipilimumab plus nivolumab is more toxic with severe side effects occurring in about the half of the patients treated. Since side effects are immune-related, depending on the organ affected and on the patients’ symptoms, they may be chronic and therefore require life-long treatment.

Two questions were considered relevant at the time of the review and three are still relevant now: 1) how to maximise benefit whilst minimise toxicity; 2) how to better identify patients who are more likely to benefit from immunotherapy.

The identification of patients potentially responsive to immunotherapy is one of the challenges clinicians are facing now. Biomarkers can help clinicians to select patients for immunotherapy avoiding unwanted side effects for those patients who are not likely to benefit from immunotherapy. The question of whether expression of PD-L1 correlates with treatment outcomes with anti-PD-1 anti-PD-L1 monoclonal antibodies has been addressed in most of the pivotal trials. PD-L1 expression has been generally assessed on tumour specimens by immunohistochemistry. A correlation between expression of PD-L1 on tumour cells and response to treatment was first seen in a phase I study of nivolumab in solid tumours and anti-PD1 expression is used to access to anti-PD1 treatment in some solid cancers.
Other biomarkers include circulating free DNA, but their predictive value in selecting patients for treatment at the moment is not known and currently under investigation in a couple fo prospective clinical trials.

With respect to immunotherapy combination, in order to enhance and optimise clinical efficacy, immunotherapy should be combined with other therapeutic modalities including chemotherapy, radiotherapy and other immunotherapy.
Chemotherapy could act in synergy with immunotherapy by promoting the release tumour antigens, the depletion of Tregs, by boosting the polarization of T-cell immunity towards TH1 responses and by increasing the activation of NK cells and their number.
Targeted agents can synergy with immunotherapy by increasing tumour antigenicity, by promoting T cells migration into the tumour, by increasing PD-L1 expression on the tumour as seen for BRAF inhibitors. MAPK inhibitors can complement T cell checkpoint therapies by enhancing tumour antigen expression, immunogenic tumour cell death, and T cell infiltration into tumours. VEGF inhibitors can complement T cell checkpoint therapies by enhancing dendritic cell maturation and activity, as well as T cell infiltration into tumours.
Radiotherapy can promote release of tumour antigen, inflammation and migration of cells of the immune system to the irradiated tumour (cold to hot tumour), can increase the number of neoantigens making the tumour more recognisable by the immune system and can promote the activation of immunogenic death pathways.
The combination of two different immunotherapeutic has many potential advantages as seen with the combination of ipilimumab plus nivolumab with the only disadvantage of increasing toxicity. However, the management of these toxicities has recently improved, and novel drugs (better tolerated) have been investigated in clinical trials including the combination nivolumab plus relatlimab which has recently received FDA approval. Other areas of development include modified T-cells or ‘CAR’ T-cell technology and oncolytic viruses.

The Authors concluded that a deeper understanding of the biology of the tumour biology in the context of immunotherapy would help guiding the clinicians for treatment and patients’ selection as a new challenge that is facing the clinical community as we have started seeing patients becoming resistant or relapsing/progressing even after a long period of benefit.

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