PI3K-AKT-mTOR inhibition in cancer immunotherapy, redux

Cancer therapies will increasingly be utilized in combination to treat advanced malignancies so as to increase their long-term efficacy in a greater proportion of patients. In particular, much attention has focused on developing targeted therapies that inhibit the PI3K-AKT-mTOR signaling network which is dysregulated in many cancer types. In addition, there is now a growing appreciation that targeting of these pathways can impact not only on cancer cells, but also host immunity. The clinical success of cancer immunotherapies targeting T-cell immune checkpoint receptors PD-1/PD-L1 has demonstrated the importance of immunoevasion as a hallmark of cancer. In this review, we discuss how PI3K-AKT-mTOR inhibitors target cancer cell biology, attenuate immune cell effector function and modulate the tumor microenvironment. We next discuss how the immunomodulatory potential of these inhibitors can be exploited through rational combinations with immunotherapies and targeted therapies

Plasmodium falciparum Merozoite Invasion Is Inhibited by Antibodies that Target the PfRh2a and b Binding Domains

Plasmodium falciparum, the causative agent of the most severe form of malaria in humans invades erythrocytes using multiple ligand-receptor interactions. The P. falciparum reticulocyte binding-like homologue proteins (PfRh or PfRBL) are important for entry of the invasive merozoite form of the parasite into red blood cells. We have analysed two members of this protein family, PfRh2a and PfRh2b, and show they undergo a complex series of proteolytic cleavage events before and during merozoite invasion. We show that PfRh2a undergoes a cleavage event in the transmembrane region during invasion consistent with activity of the membrane associated PfROM4 protease that would result in release of the ectodomain into the supernatant. We also show that PfRh2a and PfRh2b bind to red blood cells and have defined the erythrocyte-binding domain to a 15 kDa region at the N-terminus of each protein. Antibodies to this receptor-binding region block merozoite invasion demonstrating the important function of this domain. This region of PfRh2a and PfRh2b has potential in a combination vaccine with other erythrocyte binding ligands for induction of antibodies that would block a broad range of invasion pathways for P. falciparum into human erythrocytes

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Retrospective evaluation of whole exome and genome mutation calls in 746 cancer samples

Funder: NCI U24CA211006Abstract: The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) curated consensus somatic mutation calls using whole exome sequencing (WES) and whole genome sequencing (WGS), respectively. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole genome sequencing data from 2,658 cancers across 38 tumour types, we compare WES and WGS side-by-side from 746 TCGA samples, finding that ~80% of mutations overlap in covered exonic regions. We estimate that low variant allele fraction (VAF < 15%) and clonal heterogeneity contribute up to 68% of private WGS mutations and 71% of private WES mutations. We observe that ~30% of private WGS mutations trace to mutations identified by a single variant caller in WES consensus efforts. WGS captures both ~50% more variation in exonic regions and un-observed mutations in loci with variable GC-content. Together, our analysis highlights technological divergences between two reproducible somatic variant detection efforts

Tumor intrinsic and extrinsic immune functions of CD155

CD155 (PVR/necl5/Tage4), a member of the nectin-like family of adhesion molecules, is highly upregulated on tumor cells across multiple cancer types and has been associated with worse patient outcomes. In addition to well described cell-intrinsic roles promoting tumor progression and metastasis, CD155 has now been implicated in immune regulation. The role of CD155 as a potent immune ligand with diverse cell-extrinsic functions is now being defined. CD155 signaling to immune cells is mediated through interactions with the co-stimulatory immune receptor CD226 (DNAM-1) and the inhibitory checkpoint receptors TIGIT and CD96, which are differentially regulated at the cell surface on T cells and NK cells. The integration of signals from CD155 cognate receptors modifies the activity of tumor-infiltrating lymphocytes in a context-dependent manner, making CD155 an attractive target for immune-oncology. Preclinical studies suggest that targeting this axis can improve immune-mediated tumor control, particularly when combined with existing anti-PD-1 checkpoint therapies. In this review, we discuss the roles of CD155 on host and tumor cells in controlling tumor progression and discuss the possibility of targeting CD155 for cancer therapy

The promise of neoadjuvant immunotherapy and surgery for cancer treatment

Cancer immunotherapies utilizing immune checkpoint inhibitors (ICI) have demonstrated durable efficacy in a proportion of patients with advanced/metastatic cancers. More recently, the use of ICIs for the adjuvant treatment of patients with surgically resectable melanoma has also demonstrated efficacy by improving relapse-free survival and in the case of ipilimumab (anti–CTLA-4) also improving overall survival. Although promising, the effective scheduling of surgery and immunotherapy and its duration is not well elucidated. Recent preclinical studies suggest that surgery followed by adjuvant therapy might be suboptimal as compared with an approach in which immunotherapy is applied before surgery (neoadjuvant immunotherapy). Encouraging findings from early-phase clinical trials in melanoma, non–small cell lung carcinoma, and glioblastoma support the idea that neoadjuvant immunotherapy might have improved clinical efficacy over an adjuvant application. In this review, we discuss the existing rationale for the use of neoadjuvant immunotherapy, its apparent strengths and weaknesses, and implications for the design of future clinical trials

The voltage gated Ca2+-channel Cav3.2 and therapeutic responses in breast cancer

Background: Understanding the cause of therapeutic resistance and identifying new biomarkers in breast cancer to predict therapeutic responses will help optimise patient care. Calcium (Ca2+)-signalling is important in a variety of processes associated with tumour progression, including breast cancer cell migration and proliferation. Ca2+-signalling is also linked to the acquisition of multidrug resistance. This study aimed to assess the expression level of proteins involved in Ca2+-signalling in an in vitro model of trastuzumab-resistance and to assess the ability of identified targets to reverse resistance and/or act as potential biomarkers for prognosis or therapy outcome

Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease

Immunotherapy has recently entered a renaissance phase with the approval of multiple agents for the treatment of cancer. Immunotherapy stands ready to join traditional modalities, including surgery, chemotherapy, radiation, and hormone therapy, as a pillar of cancer treatment. Although immunotherapy has begun to have success in advanced cancer treatment, its scheduling and efficacy with surgery to treat earlier stages of cancer and prevent distant metastases have not been systematically examined. Here, we have used two models of spontaneously metastatic breast cancers in mice to illustrate the significantly greater therapeutic power of neoadjuvant, compared with adjuvant, immunotherapies in the context of primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8 + T cells immediately prior to and post surgery may provide a predictor of outcome. These data now provide a strong rationale to extensively test and compare neoadjuvant immunotherapy in humans. SIGNIFICANCE: We demonstrate the significantly greater therapeutic efficacy of neoadjuvant, compared with adjuvant, immunotherapies to eradicate distant metastases following primary tumor resection. Elevated and sustained peripheral tumor-specific immune responses underpinned the outcome, and blood sampling of tumor-specific CD8 + T cells immediately prior to and post surgery may provide a predictor of outcome