CIM-1 / Metromedia, Rogosin Institute - LARVOL DELTA

Usefulness of 18F-FDG PET/CT, LDH and tumor markers in the prognosis and evaluation of tumor response after RMB therapy in advanced, metastatic colorectal cancer (mCRC) (ESMO-GI 2017) - P2; "Introduction: RENCA macrobeads (RMBs) are a form of biological-systems based therapy for mCRC [USA FDA BB-IND 10091; NCT01053013]...The R and NR groups were also statistically different with respect to their mean LDH levels at Day 60 (R, 333.88+/-445.89 vs. NR, 1278.50+/- 761.9; p < 0.0001)... The data here demonstrate that LDH levels and PET-CT SUVmax changes, along with CEA and CA19-9 levels were useful in predicting and determining positive therapeutic response to RMBs in late-stage mCRC. Increasing LDH levels as a poor prognostic indicator have been reported to be useful by others, for example see Br J Cancer 116(3),318-323.2017. The correlation of PET-CT and tumor marker data with LDH levels offer further support for the clinical anti-tumor effects of the RMBs."

HEOR • Colorectal Cancer • Gastrointestinal Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor

Gut microbiome composition to predict resistance in renal cell carcinoma (RCC) patients on nivolumab. (ASCO 2018) - "Then, ICI-resistant RENCA mice were compensated with fecal microbiota transplantation (FMT) from non-PD pts or with commensals identified by WGS-MG to restore responsiveness to ICI to establish cause-effect relationship between dysbiosis and resistance. This is the largest prospective analysis so far, showing that composition of gut microbiome may predict resistance to anti-PD-1 in RCC pts. Interventions to modulate gut microbiome may represent strategies to improve clinical outcomes with ICI."

Clinical • Melanoma • Renal Cell Carcinoma

Gut microbiome composition to predict resistance in renal cell carcinoma (RCC) patients on nivolumab. (ASCO 2018) - "Then, ICI-resistant RENCA mice were compensated with fecal microbiota transplantation (FMT) from non-PD pts or with commensals identified by WGS-MG to restore responsiveness to ICI to establish cause-effect relationship between dysbiosis and resistance. This is the largest prospective analysis so far, showing that composition of gut microbiome may predict resistance to anti-PD-1 in RCC pts. Interventions to modulate gut microbiome may represent strategies to improve clinical outcomes with ICI."

Clinical • Melanoma • Renal Cell Carcinoma

LYC-55716, a first-in-class ROR agonist: Rationale and preclinical data to support clinical combinations with established immunotherapies (AACR 2018) - P1/2; "In preclinical and phase 1 clinical testing, the first-in-class, investigational oral small-molecule ROR agonist LYC-55716 has demonstrated a favorable safety profile supporting combination with other immuno-oncology agents. Ongoing clinical trials include a phase 2a trial of LYC-55716 in patients with select solid tumors (NCT02929862) and a phase 1b trial of LYC-55716 combined with pembrolizumab in patients with non-small cell lung cancer.Percentage of tumor growth inhibition induced in syngeneic murine models of cancer.Murine model Anti-PD1 alone Anti-CTLA4 alone ROR agonist alone ROR agonist + anti-PD1 ROR agonist + anti-CTLA4H22 (Liver) 30-50% >50%* 10-30% >50%* >50%*Pan02 (Pancreas) <10% 10-30% <10% 10-30%* 10-30%*CT26 (Colon) 10-30% <10% <10% <10% 30-50%B16F10 (Melanoma) 10-30% 10% 10-30% 10-30% 30-50%A230 (Lymphoma) <10% <10% 10-30% 30-50% 10%Renca (Renal) <10% 10-30% 30-50%* 30-50%* 30-50%*P<.05 vs ve

IO biomarker • PD(L)-1 Biomarker • Lymphoma • Melanoma • Non Small Cell Lung Cancer

Checkpoint inhibitor therapy in combination with the implantation of agarose encapsulated cancer cells inhibits tumor growth in a mouse model of osteosarcoma (AACR 2018) - P2,P2b; "Preliminary data suggests that continued treatment with these immune checkpoint inhibitors beyond 3 weeks prolongs the regulation of tumor growth in this model. These data support the use of anti-PD-1 in combination with the implantation of RENCA macrobeads in this mouse model of osteosarcoma, and the possibility of similar approaches in the clinic."

Checkpoint inhibition • Combination therapy • IO Biomarker • PD(L)-1 Biomarker • Preclinical • Renal Cell Carcinoma • Sarcoma

Differential proteomic responses of luminal-A and basal-like breast cancer cell lines during growth inhibition induced by co-culture with agarose encapsulated murine renal adenocarcinoma (RENCA) cells (AACR 2017) - P2,P2b; "Our evidence for this regulatory network is derived from studies demonstrating tumor growth inhibition by agarose encapsulated cancer cells (cancer macrobeads). Proteins related to apoptosis are upregulated in the MCF7 cells whereas MDA have a preference for cytoskeleton remodeling. These data support the hypothesis that distinctive tumors may respond differently to RENCA macrobead exposure at both an epigenetic and protein level, nonetheless resulting in growth inhibition."

Biosimilar • Breast Cancer • Oncology • Renal Cell Carcinoma

18F-FDG PET/CT evaluation of tumor response to the implantation of RENCA macrobeads (RMB) in phase I and II clinical trials [INDBB 10091] in advanced, treatment-resistant metastatic colorectal cancer (mCRC). (ASCO 2017) - P1,P2; "We conclude SUVs are useful in monitoring mCRC lesions response to RMB therapy. Changes in SUVs correlate w/ CEA & CA 19-9 changes. Taken together the combined data indicate anti tumor effect in these Ph 1/2a trials & offer preliminary support for our hypothesis that 18FDG can be useful in evaluating cell system therapies."

Biomarker • Clinical • P1 data • Biosimilar • Colorectal Cancer

RMB (RENCA Macrobead) therapy in advanced mCRC: Phase IIb preliminary multi-site survival findings; correlation & combination with Phase I and IIa data including imaging and lab profiles [U.S.FDA BB-IND 10091] (ESMO-GI 2018) - "...The P I/IIA trials differed from IIb in that none of their patients had been treated with regorafenib or trifluridine/tipiracil.; Mean survival for 84/89 patients (all three trials) was 41 weeks [median survival=33 weeks; SD +/-37.5 wks]...For the combined PI/IIa data, two groups of patients: R (n=25) and NR (n=9) were defined by their LDH values at days 30 and 60 after first implantation (D30, mean R value 305.92+/-284.76 vs. NR, 649.33+/- 363.60; p<0.0070), D60 (R, 333.88+/-445.89 vs. NR, 1278.50+/- 761.9; p<0.0001)... Taken together, the PI/IIa/IIb trial data are encouraging in indicating improved survival of late-stage mCRC patients with RMB treatment. The laboratory data (LDH levels, CEA and CA19-9) decreases, as well as PET-CT imaging (decreased SUVmax) support this. The data to date merit development of a Phase III randomized trial of RMB vs."

P2b data • Colorectal Cancer • Renal Cell Carcinoma

Novel, heterocyclic small molecule inhibitors of PD-1 and PD-L1 pathway (AACR 2018) - "...A number of cancer immunotherapy agents targeting PD-1/PD-L1 have been developed and approved for a number of malignancies (PD-1: Nivolumab, Pembrolizumab, PD-L1: Atezolizumab, Avelumab, Durvalumab)...In a RENCA syngeneic model, oral administration of JBI-426 at 50 mg/kg resulted in a strong tumor growth inhibition, comparable (or better) than the PD-L1 mAb, and was well tolerated...Further studies to assess additional compounds from the three chemical series are underway. The oral administration route of these PD-1/PD-L1 inhibitors would provide an attractive alternate to the currently available antibodies in treating cancer either as a stand-alone therapy or in combination with other immuno-modulatory agents, as well as other standard of care agents."

IO biomarker • PD(L)-1 Biomarker • Oncology

Combination of oncolytic vaccinia virus and immune checkpoint blockade overcomes resistance to immunotherapy in renal cell carcinoma (AACR 2018) - "Intratumoral injection of JX594 remodeled the tumor microenvironment of Renca tumor model through dynamic changes in immune system, leading to the conversion of an immunuosuppressive, non-inflamed tumor into an inflamed tumor. Finally, based on these combination results, triple combination of JX594, anti-PD-1, and anti-CTLA-4 maximized the anti-cancer immune responses and induced durable responses with improved overall survival. Collectively, we demonstrate that intratumoral injection of JX594 sensitizes non-inflamed RCC to ICI treatment through CD8+ T cell infiltration in tumor and induces anti-cancer immune responses that can overcome immunotherapy resistance."

Checkpoint inhibition • IO Biomarker • Oncolytic Virus • PD(L)-1 Biomarker • Renal Cell Carcinoma

Ganglioside GM2 mediated tumor growth, progression, and metastasis involves YAP-dependent transcriptional program (AACR 2018) - "TALEN was used to generate Renca-vGM2-syn KO cells (from a GM2-over-expressing variant of a mouse kidney cancer cell line, Renca-v). Verteporfin mediated disruption of YAP transcriptional program abrogated GM2 mediated modulation of YAP target genes. Finally, significant decrease in YAP-target gene expression in YAP/TAZ-double KO cells, but not in either YAP or TAZ (paralogue of YAP) single KOs confirm the definitive involvement of YAP/TAZ in GM2-mediated EMT.Conclusion : Our findings confirm a novel role of GM2 in triggering EMT by targeting YAP, ultimately leading to increased tumorigenic potential and metastatic activity in tumor cells."

Renal Cell Carcinoma

Characterization of immune infiltrate and checkpoint protein expression patterns in murine syngeneic tumors via multiplex immunohistochemistry (AACR 2018) - "...In this study, we applied a 7-color multiplex immunohistochemistry panel to visualize and quantify the immune infiltrate within formalin-fixed, paraffin-embedded RENCA, CT26.WT, and LL/2 tumor tissues derived from subcutaneous mouse models of renal cell carcinoma, colon carcinoma, and lung carcinoma, respectively...We characterized the tissue localization of tumor-infiltrating immune cells and analyzed the trends in co-expression and frequency patterns of immunosuppressive proteins. This study strives to better understand the underlying differences in the immunologic landscapes of these tumors, which in turn has implications for researchers studying responses to immunotherapeutic approaches and combination strategies."

IO Biomarker • PD(L)-1 Biomarker • Breast Cancer • Colorectal Cancer • Lung Cancer • Renal Cell Carcinoma

Use of RLI-15 a clinical grade fusion protein with IL-15 superagonistic activity for the activation of anti-tumor immune response (AACR 2018) - "...RLI-15 was previously shown to exhibit a potent anti-metastatic activity in B16F10 melanoma and Renca renal cell carcinoma mouse models...Furthermore, the activity of clinical-grade RLI-15 was tested in vitro on human PBMCs and the superiority over IL-2 and IL-15 stimulatory capacity has been confirmed. The complex analysis of RLI-15 behavior and of the induced anti-tumor immune response will be explored in the design of a planned Phase I clinical study in patients with both solid tumors and hematological malignancies."

Clinical • Colorectal Cancer • Leukemia • Melanoma • Prostate Cancer • Renal Cell Carcinoma

Enhanced anti-tumor activity of the combination of entinostat and NKTR214 in renal and colon cancer tumor models (AACR 2018) - "These data demonstrate that entinostat combined with NKTR-214 results in enhanced cytotoxic Teff function which translates to significant anti-tumor effects. These results provide support for clinical testing of the combination with or without additional immune checkpoint blockade."

Preclinical • Colorectal Cancer • Renal Cell Carcinoma

A tumor mitochondria vaccine protects against experimental renal cell carcinoma (AACR 2018) - "Peptide vaccines generated from mitochondrial-encoded COX1 but not from ND5 had therapeutic properties similar to RENCA mitochondrial protein preparation. Thus, TAMAs can elicit effective antitumor immune responses, potentially providing a new immunotherapeutic strategy to treat cancer."

IO Biomarker • Pancreatic Cancer • Renal Cell Carcinoma

Advantages in using orthotopic syngeneic tumor models to evaluate immune-based approaches for cancer treatment (AACR 2018) - "...Various models, such as EMT-6 (breast), MBT-2 (bladder) as well as RenCa (kidney) will be described in addition to other OT models like Hepa1-6 (liver) or PAN-02 (pancreas) models...For the PD1 targeting antibody, OT injection seemed to be the preferential site to observe increased efficacy. Attempting to correlate immune profile and response to treatment, differences in immune infiltrate between OT and SC tumors will also be presented."

Preclinical • Leukemia

Antitumor activity of lenvatinib in the renal cell carcinoma cell line RENCA model resistant to a VEGF specific inhibitor (AACR 2018) - "Lenvatinib has been approved as a monotherapy for the treatment of radioiodine-refractory differentiated thyroid cancer and in combination with everolimus for the treatment of patients with RCC treated with one prior anti-VEGF therapy in the US and EU. In conclusion, we developed a mouse RENCAVEGFR-Fc model resistant to anti-VEGF treatment, and lenvatinib showed anti-tumor activity in the resistant model as with RENCAMock model. Additional preclinical studies will be investigated to elucidate the signaling pathways associated with resistance to anti-VEGF treatment, in which lenvatinib may inhibit such as FGFR1-4, PDGFR, KIT and RET."

Preclinical • Hepatocellular Cancer • Renal Cell Carcinoma • Thyroid Cancer

HMGB1 promotes myeloid-derived suppressor cells and renal cell carcinoma immune escape. (PubMed, Oncotarget) - "When MDSCs were eliminated with Gr-1 antibody in vivo, the ability of the HMGB1 to promote tumor growth was severely impaired. Thus, our findings indicated that HMGB1 might mediate tumor immune escape by promoting MDSCs cell proliferation, which provided a novel theoretical basis for preventing RCC using HMGB1 as the target."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

A Non-integrating Lentiviral Approach Overcomes Cas9-Induced Immune Rejection to Establish an Immunocompetent Metastatic Renal Cancer Model. (PubMed, Mol Ther Methods Clin Dev) - "In this study, we demonstrate that a non-integrating lentiviral vector approach can overcome this immune rejection and allow for the growth of transduced cells in an immunocompetent host. This technique enables the establishment of a von Hippel-Lindau (VHL) gene knockout RENCA cell line in BALB/c mice, generating an improved model of immunocompetent, metastatic renal cell carcinoma (RCC)."

Journal • Preclinical • Biosimilar • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Impact of endostatin gene therapy on myeloid-derived suppressor cells from a metastatic renal cell carcinoma. (PubMed, Exp Oncol) - "These findings confirm the expansion of MDSC during metastatic progression of RCC and indicate the important role of ES in reducing MDSC and possible use of ES therapy in combined anticancer treatment."

Journal • Myeloid-derived suppressor cells • Biosimilar • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Intermittent hypoxia increases kidney tumor vascularization in a murine model of sleep apnea. (PubMed) - "Macrophages exposed to IH in vitro increased VEGF expression, whereas RENCA cells and endothelial cells did not. These findings are in keeping with previous clinical data suggesting that OSA has no effect on kidney cancer size and that the association observed between OSA and higher Fuhrman grade of renal cell carcinoma may be mediated though a proangiogenic process, with a key role of macrophages."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Stereotactic radiotherapy increases functionally suppressive regulatory T cells in the tumor microenvironment. (PubMed, Cancer Immunol Res) - "...In addition, after RT, expansion of Tregs occurred when T-cell migration was inhibited using Fingolimod, suggesting that the increased Treg frequency was likely due to preferential proliferation of intratumoral Treg after radiation...These data demonstrate that RT increased phenotypically and functionally suppressive Tregs in the TME. Our results suggest that RT might be combined effectively with Treg-targeting agents to maximize antitumor efficacy."

Journal • Biosimilar • Oncology

Contrasting effects of cyclophosphamide on anti-CTLA-4 blockade therapy in two mouse tumor models. (PubMed, Cancer Sci) - "CP augments the anti-tumor effect of anti-CTLA-4 therapy in CT26-bearing hosts, whereas CP after anti-CTLA-4 therapy attenuates this effect via induction of apoptosis in tumor-reactive T cells. Alternatively, CP-induced MDSCs can be increased by anti-CTLA-4 therapy only in RENCA-bearing hosts with an elevated level of IL-6."

Journal • Biosimilar • Colorectal Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Immunology • Inflammation • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer

Self-assembled Polypeptide Nanogels with Enzymatically Transformable Surface as an siRNA Delivery Platform. (PubMed, Biomacromolecules) - "With α-amylase added, however, VEGF mRNA knockdown by the siRNA/nanogels complexes was 50%. Our findings strongly supported the hypothesis that enzyme-responsive nanogels are promising as a therapeutic siRNA delivery platform."

Journal • Biosimilar • Genito-urinary Cancer • Oncology • Renal Cell Carcinoma • Solid Tumor • Urothelial Cancer