Combination cancer immunotherapy and new immunomodulatory targets

Abstract

Targeting immune checkpoints such as programmed cell death protein 1 (PD1), programmed cell death 1 ligand 1 (PDL1) and cytotoxic T lymphocyte antigen 4 (CTLA4) has achieved noteworthy benefit in multiple cancers by blocking immunoinhibitory signals and enabling patients to produce an effective antitumour response. Inhibitors of CTLA4, PD1 or PDL1 administered as single agents have resulted in durable tumour regression in some patients, and combinations of PD1 and CTLA4 inhibitors may enhance antitumour benefit. Numerous additional immunomodulatory pathways as well as inhibitory factors expressed or secreted by myeloid and stromal cells in the tumour microenvironment are potential targets for synergizing with immune checkpoint blockade. Given the breadth of potential targets in the immune system, critical questions to address include which combinations should move forward in development and which patients will benefit from these treatments. This Review discusses the leading drug targets that are expressed on tumour cells and in the tumour microenvironment that allow enhancement of the antitumour immune response.

Massive parallel screening of phage libraries for the generation of repertoires of human immunomodulatory monoclonal antibodies

“…16,17 Thus, further progress in the field could be made by the generation of a complete repertoire of fully human antibodies specific for many ICs to be tested preclinically alone and in appropriate combinations for rapid translation into the clinic. To this end we chose live activated hPBMCs as selectors for the generation of an unbiased library of IC binders, the Immunome Library, from which scFvs specifically recognizing a given receptor were identified by subsequent affinity selection cycles using recombinant proteins as specific baits.…”

“…Proof of concept for this approach was provided by the finding of increased efficacy of the ipilimumab and nivolumab combination versus monotherapy in the treatment of metastatic melanoma. 16,17 …”

Management of Italian Patients With Advanced Non–Small-Cell Lung Cancer After Second-Line Treatment: Results of the Longitudinal Phase of the LIFE Observational Study

“…30 TIGIT has 3 ligands, namely CD155, CD112, and CD113, which can be upregulated in tumor cells and DCs. 31 TIGIT exerts an inhibitory function in T-cell activation not only by competitively binding to CD155, but also by directly binding to CD226 to disturb transduction of stimulatory signals. It is still not fully elucidated whether TIGIT:CD112 interaction transduces inhibitory signal.…”

La résistance aux traitements antiangiogéniques

“…Dans ces modèles, une stabilité histologique et moléculaire par rapport à la tumeur d'origine peut être observée [45] et la stabilité vis-à-vis de la réponse aux traitements antiangiogéniques est également retrouvée. Cependant, la souris athymique ne présentant pas de lymphocytes cytotoxiques (LT8, lymphocytes T CD8 + ), il est important de relier ces résultats à la nature du tissu d'origine et aux données cliniques, et d'évaluer, dans les tissus, l'infiltration des LT8 et l'expression de PDL-1 (programmed deathligand 1), inhibiteur des LT8, qui peut varier selon le type de tumeur [46]. L'utilisation d'anticorps anti-PD-1 (programmed cell death-1)/ PDL-1, associée à différentes thérapies (chimiothérapie, anti-angiogéniques et radiothérapie) permet une réversion de l'anergie, cet effet étant plus évident pour des thérapies induisant une réponse inflammatoire [47].…”