Abstract Purpose: In this phase 1 portion of a first-in-human phase 1/2a study (NCT05199272), 23ME-00610 was evaluated in participants with advanced solid malignancies to determine its safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD). Exploratory biomarkers were evaluated to examine potential correlates of efficacy and safety. Patients and Methods: Eligible participants (≥18 years) were administered 23ME-00610 intravenously every 3 weeks (Q3W) using an accelerated titration design followed by a traditional 3 + 3 design, with an initial dose level of 2 mg. Results: Twenty-eight participants were enrolled across seven cohorts and received a median of four cycles of 23ME-00610. No treatment-related serious adverse events (AE) were observed, and the maximum tolerated dose was not reached. Overall, the PK of 23ME-00610 was linear and dose proportional for doses ≥60 mg, with a median terminal half-life of 13 days at 1,400 mg. Peripheral saturation of CD200R1 was observed for doses ≥60 mg. Immune-related AEs, including rash, pruritus, and hypothyroidism, were predicted by phenome-wide association studies and observed for doses ≥60 mg. A confirmed partial response was observed in a participant with well-differentiated pancreatic neuroendocrine cancer whose tumor was among those with the highest tumor CD200 expression. Conclusions: 23ME-00610 has mild-to-moderate on-target AEs and PK/PD consistent with tumor target saturation and dosing every 3 weeks. The trend for clinical benefit in participants with tumor CD200 expression suggests that 23ME-00610 inhibits CD200R1 signaling and may reverse CD200-mediated immune evasion. Based on PK/PD, safety, and preliminary antitumor activity, 1,400 mg Q3W was selected as the dose for further study. Significance: Genome-wide association studies (GWAS) of the 23andMe genetic database identified CD200R1 as a promising therapeutic target for cancer. This phase 1 study of 23ME-00610, a CD200R1 antagonist IgG1, showed acceptable safety and tolerability, PK supporting Q3W dosing, and PD and preliminary clinical activity supporting an initial recommended phase 2 dose of 1,400 mg.

Supplemental_all tables and figures

PDF file - 154K, Fig S5. Most proxVDV genes are not obviously up-regulated by rVEGF in vitro.

PDF file - 708K, Fig S2A. Histological evidence for the in vivo activity of VEGF pathway inhibitors in MDA-MB-231 tumors. Fig S2B. In vivo VEGF blockade or VEGFR-2 downstream signaling inhibition induces consistent downregulation of proxVDV genes. Fig S2C. The proxVDV gene ESM1 is an in vivo VEGF target specifically expressed in tumor-associated vasculature

PDF file - 180K, Table S1. Genes in the VDV signature, ordered by anti-VEGF response in human IBC trial. Table S2. Gene Ontology terms over-represented in VDV signature. Table S3. Summary of tumors models tested.

PDF file - 113K, Fig S1. Kinetics of anti-VEGF effects on proliferation (ki67) and tumor burden in the RIP-TβAg model.

Supplementary Data from Effects of Anti-VEGF Treatment Duration on Tumor Growth, Tumor Regrowth, and Treatment Efficacy

PDF file - 63K, Fig S3. Enrichment of VDV markers Tumor-Associated Endothelial Cells.

PDF file - 233K, Fig S4A. Validation and application of a compacted 22-gene VDV subset in human clinical samples. Fig S4B and C. Stratification of NO16966 patients by VEGF and CD31 expression levels.

PDF file - 83K, Fig S6. Effect of VDV gene expression and bevacizumab treatment in OS.

While samples of solid tumor tissue needed for morphological diagnosis and molecular testing might be lacking in a significant proportion of NSCLC patients, the reliability of tumoral PD-L1 expression on cytological imprints and liquid biopsies remains still undetermined. In this study, we aimed to compare tumoral PD-L1 expression on cytological imprints and circulating tumor cells (CTCs) with standardized PD-L1 expression testing defined by the tumor proportion score (TPS) from immunohistochemistry staining of solid tumor tissue.

Die vorliegende Stellungnahme der Expertenkommission zum Monitoring-Prozess „Energie der Zukunft“ kommentiert den achten Monitoring-Bericht zur Energiewende der Bundesregierung fur die Berichtsjahre 2018 und 2019. Die Stellungnahme bezieht sich auf den Entwurf des achten Monitoring-Berichts, welcher der Expertenkommission im Dezember 2020 vom Bundesministerium fur Wirtschaft und Energie (BMWi) in einer vorlaufigen Fassung zur Verfugung gestellt wurde. Soweit zeitlich moglich, wurden auch Anderungen des achten Monitoring-Berichts im Kontext der Ressortabstimmung berucksichtigt. Die vorliegende Stellungnahme basiert auf dem am 18. Dezember 2020 fur die Expertenkommission verfugbaren Informations- und Datenstand. Zur Dokumentation des Fortschritts bei der Umsetzung des Energiekonzepts veroffentlicht die Bundesregierung jahrlich einen faktenbasierten Monitoring-Bericht und zudem alle drei Jahre einen Fortschrittsbericht mit einer vertieften Analyse der Entwicklungen und Masnahmen sowie einem Ausblick. In diesem Jahr veroffentlicht die Bundesregierung ihren mittlerweile achten Monitoring-Bericht. Seit 2011 steht der Bundesregierung in diesem Prozess eine unabhangige Kommission aus vier Expertinnen und Experten beratend zur Seite. Die Expertenkommission zum Monitoring-Prozess „Energie der Zukunft“ legt ihrerseits jahrliche Stellungnahmen zum Fortschritt der Energiewende vor, die den Berichten der Bundesregierung beigefugt und dem Kabinett sowie dem Bundestag zugeleitet werden. Die vorliegende Stellungnahme der Expertenkommission bezieht sich auf den Entwurf des achten Monitoring-Berichts, der der Expertenkommission am 09. Dezember 2020 vom Bundesministerium fur Wirtschaft und Energie (BMWi) zur Verfugung gestellt wurde.

Abstract Background: Gastric cancer is the third leading cause of global cancer-related death, with 782,685 deaths in 2018 (Jemal, A. et al. 2018). Currently available treatments have limited benefits. Hence there’s a pressing need for more effective treatment strategies. FGFR2 gene amplification or protein overexpression in gastric cancer tumors is associated with poor prognosis (Su et al., 2014, Ahn et al., 2016). Five Prime has developed an FGFR2b-specific first-in-class humanized monoclonal IgG1 antibody, bemarituzumab (FPA144, or bema), that selectively blocks FGFR2b and triggers antibody-dependent cell-mediated cytotoxicity that showed monotherapy efficacy in a phase 1 trial (Lee et al. ASCO 2016, Catenacci et al. ASCO 2017). In this study, we evaluated the expression of FGFR2b in the context of relevant biomarkers for other approved and potential drug combinations. Methods: RNA and IHC analysis were performed using public datasets and procured tumor samples, respectively. 97 tissue samples from gastric cancer patients were assessed for expression of FGFR2b, PD-(L)1, and CD8 by IHC. In addition, TCGA-STAD database was evaluated for the status of FGFR2 overexpression and the expression of relevant targeted combination drug partners, e.g., ERBB2, PD-(L)1 and cytolytic score. For PD-(L)1 and CD8 staining, SP263 and SP57 antibodies were used, and results were reported as percent positive cells. For FGFR2b staining, the FPR2-D antibody was used (Kim, KM. et al. 2016). Staining with intensity greater than 2+ was considered FGFR2b-positive and anything less than or equal to 2 was considered negative for FGFR2b overexpression. We also investigated the literature and past and ongoing clinical trials to assess PD-(L)1 prevalence in gastric cancer and its correlation to efficacy. Results: Based on RNA expression and copy number data from samples in the TCGA-STAD dataset, combination of bemarituzumab and HER2 targeting agents would not be expected to have synergistic activity, as both populations appear mutually exclusive. In contrast, FGFR2 positive/overexpressing tumors showed good representation of high RNA expression levels of PD-(L)1, PD-1 and cytolytic score. Clinical studies using anti-PD-(L)1 therapies such as pembrolizumab indicate that most benefit (higher ORR) was observed in patients that express PD-(L)1 above a predefined threshold, measured either as a combined positive score of immune and tumor cell staining, or tumor cell staining alone (>1 as cutoff). In our dataset, we calculated % positive PD-(L)1 for both tumor cells and immune cells. Both FGFR2b+ and FGFR2b- tumors showed similar distribution of CD8 and PD-(L)1 positive cells. 60% of FGFR2b+ tumors were PD-(L)1 positive using a greater than 1% PD-(L)1 (immune cell + tumor cell) cut off. Conclusion: In our dataset, 60% of FGR2b+ population is also PD-(L)1 positive (>1%) suggesting that a combination of bemarituzumab with checkpoint inhibitors such as anti-PD-(L)1 could potentially benefit patients with FGFR2b+ tumors. Further mechanistic insight and support comes from preclinical studies (Pierce et al. AACR 2016), which showed an increase in efficacy with the combination treatment of bemarituzumab and anti-PD1 in an orthotopic mouse model. Future studies will be performed to evaluate and get a better understanding of the underlying mechanism of action of combination activity, and confirm co-expression in a larger, confirmatory dataset. Citation Format: Khushboo Sharma, Maike Schmidt, Kevin Hestir, Nerissa Mendoza, Janine Powers, James Hnatyszyn. Evaluation of FGFR2b in context of relevant biomarkers supports potential combination of anti-FGFR2b with anti-PD-(L)1 therapy in gastric cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A033. doi:10.1158/1535-7163.TARG-19-A033

The field of cancer immunotherapy has expanded rapidly in the past few years, with many new approaches entering the clinic for T cell mediated killing of tumors. Several of these clinical approaches involve the exploitation of a CD8 + T cell response against MHC I presented tumor antigens. Here, we describe the types of tumor antigens which are considered as targets in the design of T cell based therapeutic approaches, the rationale for targeting MHC I antigens and the analytical tools commonly employed for the discovery of MHC I presented peptides. The advantages and disadvantages of each approach are discussed and a perspective on the future directions of the MHC I peptide exploration field and biotherapeutic strategies is given. SIGNIFICANCE: This work is the first time a review article has been written to summarize all the various types of tumor antigens, and the analytical tools employed to discover and characterize them.

Expression of PD-L1, the ligand for T-cell inhibitory receptor PD-1, is one key immunosuppressive mechanism by which cancer avoids eradication by the immune system. Therapeutic use of blocking antibodies to PD-L1 or its receptor PD-1 has produced unparalleled, durable clinical responses, with highest likelihood of response seen in patients whose tumour or immune cells express PD-L1 before therapy. The significance of PD-L1 expression in each cell type has emerged as a central and controversial unknown in the clinical development of immunotherapeutics. Using genetic deletion in preclinical mouse models, here we show that PD-L1 from disparate cellular sources, including tumour cells, myeloid or other immune cells can similarly modulate the degree of cytotoxic T-cell function and activity in the tumour microenvironment. PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.

The small GTP-binding proteins Rac1 and Cdc42 stimulate activity of the serine/threonine kinase p21-activated kinase-1 (PAK-1) to drive growth factor signaling networks and Ras-driven tumorigenesis. Genomic amplification and over-expression of PAK1 are prevalent in luminal breast cancer and correlate with poor clinical outcome. Here we use a novel and selective small molecule inhibitor, G-5555, of the group I PAKs (PAK1, 2, and 3) to evaluate the importance of PAK1 in promoting growth of PAK1 amplified breast cancer cells. Cell lines with amplification of PAK1 were found to be more sensitive to PAK1 inhibition than non-amplified cell lines. Additionally, reverse phase protein array (RPPA) was used to assess the effects of PAK1 inhibition on a wide range of signaling pathways in both amplified and non-amplified cell lines. Reduced levels of phosphorylation of MEK S298 was observed in all cell lines exposed to G-5555 irrespective of amplification status, consistent with PAK1 inhibition in these cell lines. However, modulation of this downstream PAK1 substrate did not correlate with inhibition of cell proliferation or induction of cell death. Cell lines that showed inhibition of proliferation in response to G-5555 also showed enhanced levels of cell death along with apoptosis. Moreover, G-5555 reduced tumor growth in the PAK1 amplified MDA-MB-175 xenograft tumor model. Finally, we compared the in vitro activity of G-5555 with palbociclib, a recently approved inhibitor of the cyclin-dependent kinases CDK4 and CDK6, in PAK1 amplified luminal breast cancer cell lines. Our data supports PAK1 as an attractive target in PAK1 amplified cells and tumors and suggests that inhibiting PAK1 rather than CDK4/6 in this context may be a more attractive therapeutic strategy. Citation Format: Ong CC, Blackwood E, Jakubiak D, Daemen A, Ramaswamy S, Heise C, Schmidt M, Sanders L, Wilson TR, Huw L, Ndubaku C, Rudolph J, Hoeflich KP, Friedman L, O9Brien T. PAK-1 amplified breast cancer cell lines are preferentially sensitive to PAK inhibition with G-5555. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-04.

Abstract The small GTP-binding proteins Rac1 and Cdc42 stimulate activity of the serine/threonine kinase p21-activated kinase-1 (PAK-1) to drive growth factor signaling networks and Ras-driven tumorigenesis. Genomic amplification and over-expression of PAK1 are prevalent in luminal breast cancer and correlate with poor clinical outcome. Here we use a novel and selective small molecule inhibitor, G-5555, of the group I PAKs (PAK1, 2, and 3) to evaluate the importance of PAK1 in promoting growth of PAK1 amplified breast cancer cells. Cell lines with amplification of PAK1 were found to be more sensitive to PAK1 inhibition than non-amplified cell lines. Additionally, reverse phase protein array (RPPA) was used to assess the effects of PAK1 inhibition on a wide range of signaling pathways in both amplified and non-amplified cell lines. Reduced levels of phosphorylation of MEK S298 was observed in all cell lines exposed to G-5555 irrespective of amplification status, consistent with PAK1 inhibition in these cell lines. However, modulation of this downstream PAK1 substrate did not correlate with inhibition of cell proliferation or induction of cell death. Cell lines that showed inhibition of proliferation in response to G-5555 also showed enhanced levels of cell death along with apoptosis. Moreover, G-5555 reduced tumor growth in the PAK1 amplified MDA-MB-175 xenograft tumor model. Finally, we compared the in vitro activity of G-5555 with palbociclib, a recently approved inhibitor of the cyclin-dependent kinases CDK4 and CDK6, in PAK1 amplified luminal breast cancer cell lines. Our data supports PAK1 as an attractive target in PAK1 amplified cells and tumors and suggests that inhibiting PAK1 rather than CDK4/6 in this context may be a more attractive therapeutic strategy. Citation Format: Ong CC, Blackwood E, Jakubiak D, Daemen A, Ramaswamy S, Heise C, Schmidt M, Sanders L, Wilson TR, Huw L, Ndubaku C, Rudolph J, Hoeflich KP, Friedman L, O'Brien T. PAK-1 amplified breast cancer cell lines are preferentially sensitive to PAK inhibition with G-5555. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-04.

Einleitung/Zielsetzung: Die Nutzung der intraoperativen Untersuchung des Sentinel Lymphknotens (SLN) bei Patientinnen mit Mammakarzinom wird aktuell kontrovers diskutiert. Der Vorteil dieser Untersuchung ist die Vermeidung einer sekundären Axilla-Resektion. Darüber hinaus ist mittlerweile aus der Arbeit von Giuliano et al bekannt, dass nicht alle Patientinnen von einer Axilla-Resektion profitieren.