Copanlisib is a pan–class I phosphoinositide 3-kinase (PI3K) inhibitor with preferred activity toward PI3Kα and PI3Kδ. Despite the clear overall clinical benefit, the number of patients achieving complete remissions with the single agent is relatively low, a problem shared by the vast majority of targeted agents. Here, we searched for novel copanlisib-based combinations. Copanlisib was tested as a single agent, in combination with an additional 17 drugs in 26 cell lines derived from mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), and T-cell lymphomas. In vivo experiments, transcriptome analyses, and immunoblotting experiments were also performed. Copanlisib as a single agent showed in vitro dose-dependent antitumor activity in the vast majority of the models. Combination screening identified several compounds that synergized with copanlisib. The strongest combination was with the B-cell lymphoma 2 (BCL2) inhibitor venetoclax. The benefit of the combination over single agents was also validated in an MZL xenograft model and in MCL primary cells, and was due to increased induction of apoptosis, an effect likely sustained by the reduction of the antiapoptotic proteins myeloid cell leukemia 1 (MCL1) and BCL-XL, observed in MCL and MZL cell lines, respectively. These data supported the rationale for the design of the Swiss Group for Clinical Cancer Research (SAKK) 66/18 phase 1 study currently exploring the combination of copanlisib and venetoclax in relapsed/refractory lymphomas.

Because of the key relevance of protein–protein interactions (PPI) in diseases, the modulation of protein-protein complexes is of relevant clinical significance. The successful design of binding compounds modulating PPI requires a detailed knowledge of the involved protein-protein system at molecular level, and investigation of the structural motifs that drive the association of the proteins at the recognition interface. These elements represent hot spots of the protein binding free energy, define the complex lifetime and possible modulation strategies. Here, we review the advanced technologies used to map the PPI involved in human diseases, to investigate the structure-function features of protein complexes, and to discover effective ligands that modulate the PPI for therapeutic intervention.

Purpose: This study was aimed at evaluating the feasibility, safety, immunological and clinical responses in patients with Follicular lymphoma (FL) treated with monocyte-derived dendritic cells generated in the presence of interferon-alpha and GM-CSF (IFN-DC) in combination with low doses of Rituximab (R). Experimental design: Firstly, we analyzed in vitro and in vivo the immunological properties of IFN-DC against FL. Thus, we performed a phase I trial in 8 refractory and relapsed FL patients based on sequential intranodal injections of low-dose of R and unloaded IFN-DC and report the safety, clinical and immunological results of the enrolled patients. Results: Preclinical studies indicated that IFN-DC can synergize with R leading to increased cytotoxicity and T cell tumor infiltration. The clinical evaluation showed that the combined treatment was totally safe. The overall response rate was 50%, PET-negative complete response rate 37% and remission is still ongoing in 2/4 of responding patients (median follow-up 26 months, range 11-47). Notably, following the combined therapy all patients showed induction/enhancement of T cell responses by CD107 degranulation or IFN-g ELISPOT assay against patient-specific tumor IGHV sequences. Conclusions: These results represent the proof-of-principle on the effectiveness of unloaded IFN-DC in inducing durable clinical responses and promoting induction of tumor specific peripheral T cells, thus suggesting the occurrence of an effective endogenous antitumor vaccination. The overall findings indicate that some unique properties of IFN-DC can be successfully exploited to induce/enhance antitumor responses, thus representing a valuable antitumor strategy for novel and more effective combination therapies in cancer patients. Translational relevance: The development of protocols of in situ cancer immunotherapy aimed at inducing an endogenous vaccination is currently regarded as a practical and promising antitumor strategy, with potential advantages with respect to the use of defined tumor antigens for inducing a broader antitumor immunity, potentially targeting also neoantigens emerging during tumor progression and therapies. This study represents the first evidence on the safety and clinical effectiveness of IFN-DC, a unique type of DC rapidly generated from monocytes under simple GMP conditions and endowed with special immunostimulatory properties. Combined with low doses of intranodal injection of R, IFN-DC induced clinical response in cancer patients and promoted the induction of tumor specific T cells. All this implies the occurrence of an endogenous antitumor vaccination possibly resulting in clinical response. The findings suggest that IFN-DC are a good candidate for a selective clinical use in combination therapies in cancer patients Keywords: dendritic cells; follicular lymphoma (FL); immune system. ABSTRACT copanlisib/crizotinib (3/4 synergisms). All but one of the non ALCL-ALK+ cell lines achieved a synergism with copanlisib/ruxolitinib. Copanlisib/brentuximab vedotin was...