Novel Checkpoints and Cosignaling Molecules in Cancer Immunotherapy

Abstract

The recent demonstration of the antitumor efficacy of checkpoint protein inhibition has resulted in the approval of blocking antibodies against the programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway in multiple different histologic findings. Therapeutic successes with PD-1/PD-L1 antibodies in melanoma and lung cancer have been followed by approvals in bladder, renal, and head and neck cancers and Hodgkin lymphoma, with others undoubtedly to come. However, PD-1 is only one of many checkpoints and agonistic regulatory molecules expressed on T cells by which maintenance of the balance between costimulatory and coinhibitory signaling pathways is perturbed in cancer. The manipulation of many of these molecules in cancer patients might be associated with clinical benefit. The majority of the T-cell cosignaling receptors belong to either the immunoglobulin superfamily or the tumor necrosis factor receptor superfamily. A total of 29 immunoglobulin superfamily and 26 tumor necrosis factor receptor superfamily cosignaling receptors have been identified that are expressed on T cells, providing fertile ground for development of inhibitory or agonistic antibodies and small molecules as cancer therapeutics. In the current work, we focus on some of the most promising new checkpoints and agonistic or cosignaling molecules that are in early clinical development as single agents or in combinations with PD-1/PD-L1, cytotoxic T-lymphocyte-associated protein 4 blockade, or chemotherapy with an emphasis on those that have reached the clinic and on important targets that are in late preclinical development.

Checkpoint Inhibition in Non-Hodgkin's Lymphoma

“…Literally dozens of novel agents are on the edge to enter clinical development [83] and the number of potential combinations is far beyond any realistic chance to evaluate them in prospective trials. This requires a rigid concentration on the most promising candidates and combinations, to avoid paralysis of the entire development [98].…”

“…However, as results in HD did also not seem superior to single-agent nivolumab, the role of ipilimumab at least needs to be questioned in this combination [81]. An additional approach would be the combination with drugs that affect the interaction with other cells such as the antigen-presenting cells, which is achieved with drugs inhibiting CD137, OX40, or CD40, or many others [82,83]. As an example, urelumab, an anti-CD137 agonistic antibody that has shown moderate single-agent activity, was combined with nivolumab and tumor control was observed [84].…”

Checkpoint-Inhibition bei Non-Hodgkin-Lymphom

“…antigenpräsentierenden Zellen, beeinflussen. Dies lässt sich mit Arzneimitteln erreichen, die hemmend auf CD137, OX40, CD40 oder viele andere wirken [82,83]. Beispielsweise war unter der Kombinationstherapie von Urelumab, einem agonistischen anti-CD137-Antikörper, der als Einzelwirkstoff mäßige Aktivität gezeigt hat, und Nivolumab eine Tumorkontrolle zu beobachten [84] …”

“…Diese müssen jedoch noch eingehender untersucht werden, um CI optimal einsetzen zu können [97]. Buchstäblich Dutzende neuartige Wirkstoffe befinden sich derzeit kurz davor, in das Stadium der klinischen Entwicklung einzutreten [83] und die Zahl potenzieller Kombinationen übersteigt bei weitem jede realistische Möglichkeit, sie in prospektiven Studien näher zu untersuchen. Daher ist eine strenge Konzentration auf die aussichtsreichsten Kandidaten und Kombinationen erforderlich, um eine Paralyse der gesamten Entwicklung zu vermeiden [98].…”

Informatics for Cancer Immunotherapy

“…The relatively recent success of checkpoint blockade therapies in melanoma [332] , followed by other malignancies [333][334][335][336] , has motivated a resurgence of research into immune checkpoint receptors and their ligands [337,338] . The FDA has approved antibodies targeting CTLA-4 and PD-1/PD-L1, and new immune checkpoint targets are the subject of active investigation [339][340][341][342][343] .…”