The perspective of immunotherapy: new molecules and new mechanisms of action in immune modulation.

Targeting CTLA-4, the patriarch of immune checkpoint modulators, is currently the only immunotherapeutic approach that has achieved significant clinical benefit in melanoma phase III trials. In this review, recent new ideas about the mechanism of action of anti-CTLA antibodies, other new molecules to target, and rationales for combination therapies will be discussed.

Although the clinical efficacy of the anti-CTLA-4 monoclonal antibody (mAb) ipilimumab is meanwhile without doubt, its mechanism of action is still not fully understood. Recent data indicate that, besides modulation of the TCR signal, CTLA-4 mAbs can mediate regulatory T-cell depletion in an Fc gamma receptor dependent manner.Blockade of the molecules PD-1 and PD-L1 has given promising clinical responses (and this beyond melanoma), whereas their complex expression and interaction pattern makes a clear statement about the mechanism of action challenging.Additional other co-inhibitory and co-stimulatory molecules have been identified recently. Combinations of immune checkpoint modulators themselves or with other therapies, such as adoptive cell therapy, targeted therapy or radiotherapy, will improve the outcomes further.

Immune checkpoint blockade is currently the most promising systemic therapeutic approach to achieve long-lasting responses or even cure in melanoma and other malignancies.