Metastatic Renal Carcinoma Research Articles

Carbonic Anhydrase IX (CA9) Overexpression and Negative PAX8 Staining Can Be Used to Confirm Hemangioblastomas

Abstract Introduction/Objective Hemangioblastomas are indolent brain tumors consisting histologically of atypical stromal cells and a large number of blood vessels lined by endothelial cells. The tumors are often associated with either von Hippel- Lindau (VHL) syndrome or sporadic mutation of VHL genes. As CA9 is a marker of the hypoxic inducible factor-alpha1 cascade, its overexpression has been well known to present in clear cell renal cell carcinoma that involves the mutation of VHL gene. A few studies demonstrate overexpression of CA9 in hemangioblastomas, but not in other primary brain tumors such as gliomas and meningioma. Our two cases were used to determine if positive CA9 and negative PAX8 immuno-stains were useful markers to support the diagnosis of hemangioblastomas. Methods/Case Report One patient was a 50-year-old man and the other patient was a 75-year-old man. Two lesions were identified in the cerebellum with typical appearance of vascular channels intermingled with atypical stromal cells showing clear cell cytoplasm. The endothelial cells were positive for CD34 and ERG. The stromal cells were weakly positive for inhibin but negative for the endothelial markers GFAP, pancytokeratin and PAX8, ruling out primary glioma and metastatic clear cell renal carcinoma. The atypical stromal cells with clear cytoplasm in both tumors, however, showed strong and diffuse membranous staining for CA9 (3+). The overall findings supported the morphologic diagnosis of hemangioblastomas in both patients. Results (if a Case Study enter NA) NA Conclusion Our preliminary data indicates that positive CA9 and negative PAX8 stains are a useful pair of markers to support a diagnosis of hemangioblastoma and differentiate them from metastatic clear cell renal cell carcinoma. Additionally, CA9 can help confirm the diagnosis of hemangioblastoma when inhibin is weak or nearly negative.

An Exogenous Ketone Ester Slows Tumor Progression in Murine Breast and Renal Cancer Models.

Ketone esters (KEs) exhibit promise as anti-cancer agents but their impact on spontaneous metastases remains poorly understood. Although consumption of a ketogenic diet (KD) that is low in carbohydrates and high in fats can lead to KE production in vivo, the restrictive composition of KDs may diminish adherence in cancer patients. We investigated the effects of an exogenous ketone ester-supplemented (eKET), carbohydrate-replete diet on tumor growth, metastasis, and underlying mechanisms in orthotopic models of metastatic breast (4T1-Luc) and renal (Renca-Luc) carcinomas. Mice were randomized to diet after tumor challenge. Administration of KEs did not alter tumor cell growth in vitro. However, in mice, our eKET diet increased circulating β-hydroxybutyrate and inhibited primary tumor growth and lung metastasis in both models. Body composition analysis illustrated the overall safety of eKET diet use, although it was associated with a loss of fat mass in mice with renal tumors. Immunogenetic profiling revealed divergent intratumoral eKET-related changes by tumor type. In mammary tumors, Wnt and TGFβ pathways were downregulated, whereas in renal tumors, genes related to hypoxia and DNA damage repair were downregulated. Thus, our eKET diet exerts potent antitumor and antimetastatic effects in both breast and renal cancer models, albeit with different modes of action and physiologic effects. Its potential as an adjuvant dietary approach for patients with diverse cancer types should be explored further.

Initial Frontal Sinus and Orbit Tumor Signaling Late Distant Metastasis in Kidney Cancer.

Although metastases to the paranasal sinuses are exceedingly rare, when they do occur, renal clear cell carcinoma is the most frequent primary tumor involved. The aim of this work was to present a case of metastatic clear cell renal carcinoma in the frontal sinus and orbit region, 7 years after the initial diagnosis and treatment. The patient was referred to our clinic due to drooping of the left eyelid and displacement of the left eyeball. Computed tomography revealed an expansive lesion in the left frontal sinus and orbit, causing destruction of its anterior, lateral, and roof walls. Profuse bleeding from the tumor and left orbit hindered a comprehensive assessment of tumor extension into the orbit and residual tumor size. Therefore, complete tumor removal was not possible; instead, reduction was achieved. Subsequent histopathologic and immunohistochemical analysis confirmed the lesion as a metastasis of renal cell carcinoma in the sinonasal tract. Unfortunately, 10 weeks later, the patient passed away. Treatment of metastatic clear cell renal carcinoma depends on the localization of the disease as well as the overall condition of the patient. If there is a solitary metastatic lesion, as in the case of the sinonasal region, surgical treatment is recommended. Metastasis of clear cell renal carcinoma to the sinonasal region is a rare occurrence; however, it is essential to consider it in cases of rapidly growing tumor masses, typically presenting with symptoms such as epistaxis and nasal obstruction.

Can Cytoreductive Nephrectomy Improve Outcomes of Nivolumab Treatment in Patients with Metastatic Clear-Cell Renal Carcinoma?

Background: This study aimed to investigate the effect of cytoreductive nephrectomy (CN) on the survival outcomes of nivolumab used as a subsequent therapy after the failure of at least one anti-vascular endothelial growth factor (VEGF) agent in patients with metastatic clear-cell renal-cell carcinoma (ccRCC). Methods: We included 106 de novo metastatic ccRCC patients who received nivolumab after progression on at least one anti-VEGF agent. Multivariate Cox regression analysis was performed to investigate the factors affecting survival in patients receiving nivolumab. Results: Of the 106 de novo metastatic ccRCC patients, 83 (78.3%) underwent CN. There were no statistical differences between the two groups in terms of age, gender, Eastern Cooperative Oncology Group (ECOG) score, tumor size, International Metastatic RCC Database Consortium (IMDC) risk group, number of previous treatment lines, first-line anti-VEGF therapy, or metastasis sites (p = 0.137, p = 0.608, p = 0.100, p = 0.376, p = 0.185, p = 0.776, p = 0.350, and p = 0.608, respectively). The patients who received nivolumab with CN had a longer time to treatment discontinuation (TTD) [14.5 months, 95% confidence interval (CI): 8.6-20.3] than did those without CN 6.7 months (95% CI: 3.9-9.5) (p = 0.001). The median overall survival (OS) was 22.7 months (95% CI: 16.1-29.4). The patients with CN had a median OS of 22.9 months (95% CI: 16.3-29.4), while those without CN had a median OS of 8.1 months (95% CI: 5.6-10.5) (p = 0.104). In the multivariate analysis, CN [hazard ratio (HR): 0.521; 95% CI: 0.297-0.916; p = 0.024] and the IMDC risk score (p = 0.011) were statistically significant factors affecting TTD; however, the IMDC risk score (p = 0.006) was the only significant factor for overall survival. Conclusions: Our study showed that the TTD of nivolumab was longer in metastatic ccRCC patients who underwent cytoreductive nephrectomy.

2858: Role of SBRT in patients with metastatic renal carcinoma: experience in our center

2858: Role of SBRT in patients with metastatic renal carcinoma: experience in our center

Metastatic renal carcinoma in a horse presented for lameness examination and suspected pneumonia

AbstractEquine renal cell carcinoma (RCC) is a rare and poorly understood condition, making the diagnosis challenging. We present a case of a 16‐year‐old Warmblood gelding referred for lameness and suspected pneumonia. The horse exhibited diverse non‐specific symptoms, including pyrexia, coughing, weight loss and lameness. Diagnostic imaging revealed an osseous neoplastic lesion and lung metastasis. Postmortem confirmed metastatic renal carcinoma. This case underscores the difficulty of RCC diagnosis due to non‐specific clinical signs, necessitating a comprehensive approach involving clinical, imaging and histopathological findings. RCC offers limited treatment options as it is typically diagnosed at advanced stages, leading to a poor prognosis and euthanasia. Increased awareness and research are crucial for early detection and better understanding of this rare equine disease.

Concomitant Administration of VEGFR Tyrosine Kinase and Proton Pump Inhibitors May Impair Clinical Outcome of Patients With Metastatic Renal Cancer

IntroductionThe administration of proton pump inhibitors (PPIs) is a common practice to reduce gastro-esophageal adverse events associated with drug treatments but may impair absorption and exposure to oncology drugs. This study investigated the effect of concomitant administration of PPIs and pazopanib, sunitinib and cabozantinib on survival of patients with metastatic clear cell renal carcinoma (mRCC). Patients and MethodsTotal 451 patients receiving pazopanib, sunitinib and cabozantinib as first line treatment were enrolled in this retrospective study. Patients were defined as “no concomitant PPIs (PPI−)” if no PPIs were administered during TKIs, and as “concomitant PPIs (PPI+)” if the administration of PPIs was at least 75% of the time during which TKIs were given. ResultsEighty patients administered pazopanib were PPI− and 86 PPI+; no difference in PFS was observed (10.7 vs. 11.9 months, P = .79). If patients were stratified as short (n = 89) and long (n = 77) responders, there was a significant difference in terms of PFS in PPI+ (n = 47) versus PPI− (n = 30) in long responders, being 24.7 versus 38 months (P = .04), respectively. In the sunitinib cohort, no significant difference of PFS in PPI+ (n = 102) versus PPI− (n = 131) was found, being 11.3 versus 18.1 months, respectively (P=0.15). In the cabozantinib cohort, there was a statistically significant difference in PFS of PPI+ versus PPI− (6 months vs. not reached, P = .04). No correlation with adverse events was found. ConclusionsThis study demonstrates an association between PPIs and impaired PFS in mRCC patients given pazopanib and cabozantinib and recommends caution on their concomitant use.

Pazopanib-induced hypothyroidism in a patient with metastatic renal carcinoma

Pazopanib-induced hypothyroidism in a patient with metastatic renal carcinoma

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

CRP kinetics to predict long-term efficacy of first-line immune-checkpoint inhibition combination therapies in metastatic renal cell carcinoma: An updated multicenter real-world experience applying different CRP kinetics definitions.

405 Background: Although biomarkers predicting therapy response in 1st line metastatic renal carcinoma (mRCC) therapy remain to be defined, C-reactive protein (CRP) kinetics have recently been associated with immunotherapy (IO) response. To assess the predictive and prognostic power of two contemporary CRP kinetics definitions in a large, real-world 1st line mRCC cohort. Methods: mRCC patients treated with IO-based 1st line therapy within 5 years were retrospectively included in this multi-center study. According to Fukuda et al., patients were defined as ‘CRP flare-responder’, ’CRP responder’ and ‘non-CRP responder’; according to Ishihara et al., as ‘normal’, ‘normalized’ and ‘non-normalized’ based on their early CRP kinetics. Patient and tumor characteristics were compared, and treatment outcome was measured by overall (OS) and progression-free survival (PFS), including multivariable Cox regression analyses. Results: Out of 316 mRCC patients, 227 (72%) were assigned to CRP groups according to Fukuda. Both CRP flare- (HR [Hazard ratio]: 0.59) and CRP responders (HR: 0.52) had a longer PFS, but not OS, than non-CRP responders. According to Ishihara, 276 (87%) patients were assigned to the respective groups, and both normal and normalized patients had a significantly longer PFS and OS, compared to non-normalized group. Conclusions: Different early CRP kinetics may predict therapy response in 1st line mRCC therapy in a large real-world cohort. However, further research regarding the optimal timing and frequency of measurement is needed.

Multiomics approach for patient stratification and novel target identification in metastatic clear cell renal carcinoma (Meet-URO 31).

TPS498 Background: The choice of the best treatment in first line metastatic clear-cell renal cell carcinoma (mccRCC) patients is becoming an issue, since no biomarkers are available to guide the treatment allocation strategy. Recently there has been a great deal of interest in Artificial Intelligence (AI) systems and their ability to process heterogeneous data for both classification and prediction purposes. An additional fields of interest in genitourinary oncology are also liquid biopsy and radiomics. Non-invasive liquid biopsy methods are able to detect and characterize circulating cell-free DNA (cfDNA), extracellular vesicles (EV) associated RNAs and circulating tumor cells (CTCs) and to allow longitudinal evaluation of tumor evolution whereas radiomics may provide a novel approach to develop predictive tools by correlating imaging features to tumor characteristics including histology, tumor grade, genetic patterns and molecular phenotypes, as well as clinical outcomes. We hypothesize that AI can be used to integrate data obtained from radiomics, genomic and transcriptomic analysis of CT scan, neoplastic tissues and circulating cell-free DNA or microvescicle-associated RNA with the purpose of defining an optimal allocation strategy for patients with mccRCC undergoing first-line therapy and identifying novel targets in mccRCC. Methods: This is a multicenter Italian prospective translational study evaluating transriptomic, genomics and radiomics in treatment-naïve advanced ccRCC patients. Subjects will be screened to identify a total of 100 patients eligible for the study, candidate to receive first-line treatment as per investigator’s choice according to clinical practice. Tumoral tissue, plasma samples and radiological exams will be collected at baseline, at 3 months, at the time of first radiological evaluation and at disease progression (PD) to provide a comprehensive molecular profile and radiomic features extrapolation, respectively. AI systems will be used to build a genomic-radiomic profile of patients to correlate to treatment response. The planned sample size of 100 patients will allow an exploratory analysis of the prognostic and predictive performance of the "multiomic" classifier, to be subsequently validated in a larger expansion cohort of patients. Through the above research we are confident to provide proof of concept that AI is able to combine the information from genomics, transcriptomic and radiomics to provide an opportunity for a molecularly driven patients' stratification, aiming to choose the ideal first-line systemic treatment for each patient. Enrollment has already begun and the trial has enrolled 15 of the planned 100 patients. Clinical trial information: NCT05782400 .

Circulating tumor cells as a predictor and prognostic tool for metastatic clear cell renal carcinoma: An immunocytochemistry and genomic analysis

BackgroundTreatment of metastatic clear cell renal carcinoma (mccRCC) has changed dramatically over the past 20 years, without improvement in the development of biomarkers. Recently, circulating tumor cells (CTCs) have been validated as a prognostic and predictive tool for many solid tumors. ObjectiveWe evaluated CTCs in blood samples obtained from patients diagnosed with mccRCC. Comparisons of CTC counts, protein expression profiling, and DNA mutants were made in relation to overall survival and progression-free survival. MethodsCTCs were isolated from 10 mL blood samples using the ISET® system (Isolation by SizE of Tumor Cells; Rarecells, France) and counted. Protein expression was evaluated in immunocytochemistry assays. DNA mutations were identified with next generation sequencing (NGS). ResultsBlood samples (10 mL) were collected from 12 patients with mccRCC before the start of first-line systemic therapy, and again 30 and 60 days after the start of treatment. All 12 patients had CTCs detected at baseline (median, 1.5 CTCs/mL; range: 0.25–7.75). Patients with CTC counts greater than the median had two or more metastatic sites and exhibited worse progression-free survival (19.7 months) compared to those with CTC counts less than the median (31.1 months). Disease progression was observed in 7/12 patients during the study. Five of these patients had baseline CTC counts greater than the median, one had higher CTC levels at the second blood collection, and one patient had CTCs present at 1 CTC/mL which positively stained for PD-L1, N-cadherin, VEGF, and SETD2. CTC DNA from six patients with worse outcomes was subjected to NGS. However, no conclusions could be made due to the low variant allele frequencies. ConclusionDetection of CTCs in patients with mccRCC receiving first-line treatment is a feasible tool with prognostic potential since increased numbers of CTCs were found to be associated with metastasis and disease progression.

P180 - Beyond IMDC stratification: potential alternative prognostic factors in metastatic renal cells carcinoma

P180 - Beyond IMDC stratification: potential alternative prognostic factors in metastatic renal cells carcinoma

P160 - Clinical characterisation, prognosis, and assessment of predictive score for response to treatment of metastatic renal cells carcinoma with rhabdoid component

P160 - Clinical characterisation, prognosis, and assessment of predictive score for response to treatment of metastatic renal cells carcinoma with rhabdoid component

SAT479 A Case of Thyroiditis Cause by Cabozantinib

Abstract Disclosure: S. Bulchandani: None. N. Janicic-Kahric: None. Introduction: Thyroiditis is an inflammatory disease of the thyroid; the cause can be autoimmune, infectious or drug induced. Patients can have an initial phase of hyperthyroidism (thyrotoxicosis) attributed to the release of preformed thyroid hormone from damaged thyroid cells. This can be followed by hypothyroidism, when the thyroid stores are depleted, and then eventual restoration of normal thyroid function. Some patients may develop permanent hypothyroidism.1 We report a case of thyroiditis caused by cabozantinib. CASE REPORT: 39-year-old female presented with abdominal pain, vomiting and palpitations. Past medical history was significant for metastatic clear cell renal carcinoma. Eight weeks before the presentation, she had started on cabozantinib 60 mg daily as part of therapy for her renal carcinoma. On presentation, the patient’s temperature was 36.6 Celsius, heart rate was 118 beats/minute, blood pressure was 114/84 mm Hg and oxygen saturation was 100% on room air. Laboratory evaluation was notable for white blood cell count of 12.3 k/uL, Hemoglobin of 16.5g/dl, Platelet count of 573 k/uL bicarbonate level of 13 mmol/L, anion gap 24 mmol/L, Total bilirubin of 0.6 mg/dl, Aspartate aminotransferase of 36 units/L, Alanine aminotransferase of 30 units/L, Alkaline phosphatase of 121 units/L. Thyroid function tests revealed thyroid stimulating hormone (TSH) which was low at 0.045 uIU/ml and free thyroxine level (Free T4) which was elevated at 4.29 ng/dl. Thyroid function tests performed eight weeks prior to presentation showed TSH of 6.9 uIU/ml, attributed to immunotherapy that the patient received 1 month prior. She was admitted and received intravenous fluids. Prednisone at 40 mg orally daily was initiated. Labs demonstrated a decrease in Free T4 level. She was discharged on a tapering course of prednisone. Free T4 one week later was normal at 1.35ng/dl. Repeat laboratory evaluation three weeks later revealed that the patient had developed hypothyroidism with TSH level of 8.7 uIU/ml and she was started on 50 micrograms of levothyroxine. Cabozantinib was discontinued. Discussion: Tyrosine Kinase inhibitor therapy can result in clinically significant thyroid dysfunction. Cabozantinib treatment can result in thyroid dysfunction varying from subclinical hypothyroidism to symptomatic thyrotoxicosis. Early detection and close follow-up are essential to provide adequate management2 Presentation Date: Saturday, June 17, 2023

Survival of patients with clear cell renal carcinoma according to number and location of organ-specific metastatic sites

BackgroundThe prognostic significance of number and location of organ-specific metastatic sites in treated metastatic clear cell renal carcinoma (ccmRCC) patients is object of debate. The current study aimed to test the association between number and location of organ-specific metastatic sites and overall survival (OS) in ccmRCC. Materials and methodsWithin Surveillance, Epidemiology and End Results database (2010–2018), all ccmRCC patients treated with cytoreductive nephrectomy and/or systemic therapy were identified. Kaplan-Meier plots and Cox regression models focused on: A). number of organ-specific metastatic sites: solitary vs. 2 vs. 3 or more; B). solitary organ-specific metastatic sites (lung vs. bone vs. liver vs. brain); C). combinations of 2 and 3 or more different organ-specific metastatic sites. ResultsOf 4,527 patients (median OS: 19 months), 3,054 (67%) harbored solitary organ-specific metastatic sites (27 months) vs. 1,153 (25%) combinations of 2 different organ-specific metastatic sites (12 months) vs. 320 (8%) combinations of 3 or more different organ-specific metastatic sites (7 months). In patients with solitary organ-specific metastatic sites, bone metastases portended the longest median OS (median OS: 31 months) vs. liver metastases portended the shortest median OS (16 months). Both were independent predictors of OS (multivariable hazard ratio, bone: 0.87; liver: 1.21). Median OS was similarly poor in patients with combinations of 2 different organ-specific metastatic sites (9–13 months), regardless of their location. The same pattern applied to patients with combinations of 3 or more different organ-specific metastatic sites (6–7 months). ConclusionsSolitary organ-specific metastatic sites portend the most favorable OS (16–31 months). Solitary bone metastases yield the longest vs. liver metastases the shortest OS. Invariably poor OS applies to combinations of 2 (9–13 months), as well as 3 or more different organ-specific metastatic sites (6–7 months), regardless of their location.

Efficacy and safety evaluation of immunotherapy combined with targeted therapy as second-line treatment in patients with metastatic non-clear cell renal cell carcinoma

Objective: This study aimed to evaluate the efficacy and safety of programmed death-1 (PD-1) inhibitor combined tyrosine kinase inhibitor (TKI) therapy versus TKI monotherapy as the second-line regimen for patients with metastatic non-clear cell renal carcinoma (nccRCC) who failed first-line TKI therapy. Methods: The clinicopathological data of 67 patients with metastatic nccRCC who failed first-line TKI therapy between October 2011 and September 2020 were retrospectively analyzed, including 22 patients who received TKI monotherapy and 45 patients who received TKI plus PD-1 inhibitor as the second-line therapy. The efficacy was assessed according to Response Evaluation Criteria in Solid Tumors version 1.0/1.1 (RECIST 1.0/1.1), the Kaplan-Meier method was used to plot the survival curves, and the Log rank test was used to analyze the differences in the survival between the two groups. Treatment-related adverse events (AEs) after treatment were observed in both groups. Results: The overall objective response rate (ORR) and disease control rate (DCR) were 37.3% (25/67) and 56.7% (38/67), respectively. The overall second-line progression-free survival (PFS) was 7.7 months and Overall Survival (OS) was 25.2 months. The ORR and DCR of patients in the combination therapy group were 48.9% (22/45) and 71.1% (32/45), respectively, which were significantly improved compared with the TKI monotherapy group [13.6% (3/22) and 27.3% (6/22), respectively] (P=0.007 and P=0.001, respectively). The median PFS of 9.2 months for second-line treatment was longer in patients in the combination therapy group than in the TKI monotherapy group (5.2 months, P=0.001), but the median OS was not statistically different between the two groups (28.2 months vs 20.8 months, P=0.068). Common treatment-related AEs included hypertension, diarrhea, fatigue, stomatitis, hand-foot syndrome, and hypothyroidism. The incidence of hypothyroidism was higher in the combination therapy group [40.0% (18/45)] than in the TKI monotherapy group [22.7% (5/22), P=0.044]; the incidence of other treatment-related AEs between the two groups were not statistically significant (all P>0.05). Conclusion: Immune-targeted combination therapy was more effective than TKI monotherapy alone and was well tolerated in the treatment of metastatic nccRCC patients who failed first-line TKIs.

Primary hypoadrenalism and thyroiditis in metastatic renal carcinoma in Pembrolizumab (PD-1inhibitor) and Axitinib (VEGFR inhibitor) therapy

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract LB101: Cell-generated IL12 combined with PD-1 inhibition produces local and abscopal immune activation to eradicate metastatic melanoma and pancreatic cancer

Abstract Background: Cytokines have been FDA approved for cancer immunotherapy for treatment of metastatic melanoma and renal carcinoma for over 30 years (1, 2). To overcome stability and toxicity limitations seen with high dose cytokine immunotherapy, we developed a delivery platform, called cytokine factories, composed of genetically engineered epithelial cells encapsulated in biocompatible polymers. These clinically translatable cytokine factories are able to safely deliver high local doses of pro-inflammatory cytokines, such as interleukin-12 (IL12), and allow for controlled and predictable dosing in vivo. Results: Tumor-adjacent administration of IL12-based cytokine factories in vivo created a high local cytokine concentration (IP space) without substantial leakage into the systemic circulation. In addition, administration of cytokine factories in combination with anti-PD1 checkpoint inhibitors caused reduction of tumor burden by over 60% when delivered as a monotherapeutic to mice with metastatic melanoma (3). Further, when administered in combination with local anti-PD1 checkpoint inhibitors, these cytokine factories led to reduction of intraperitoneal tumor burden by over 80% after only 10 days of treatment. Finally, we evaluated the ability of this therapy to treat pancreatic tumors which are notoriously known to be resistant to immunotherapy. We found that the median survival for control animals was 45 days. However, 8/8 of animals treated with IL12 cytokine factories survived throughout the duration of the study (110 days), demonstrating a significant extension of overall survival time. Conclusions: Our findings demonstrate efficacy of cytokine factories as single agent and combination therapeutics in preclinical animal models and provide rationale for future clinical testing for the treatment of metastatic peritoneal cancers in humans.

Correlation of the immune tumor microenvironment (I-TME) with gene expression profiles as prognostic and predictive factors in patients (pts) with metastatic renal carcinoma (mRCC) treated with immunotherapy (Meet-URO 18 I-TME study).

TPS753 Background: Several studies suggested that response to immunotherapy may be influenced by many factors, including peripheral blood biomarkers, the composition of I-TME and different molecular expression pathways. In mRCC patients, immunotherapy has become part of clinical practice, but the identification of patients most likely to respond to checkpoint inhibitors is still an unmet clinical need. Moreover, there are no validated and clinically applicable gene expression panels as prognostic and/or predictive response biomarkers. To date, three major groups of immune-related gene expression were identified in mRCC: the angiogenesis pathway, the T-effector pathway and the mixed pathway (doi: 10.1038/s41598-020-58804-y). Each group of gene expression seems to be responsible for a different type of immune response in the I-TME. However, a significant association with treatment response to immunotherapy has not yet been demonstrated. Methods: The Meet-URO 18 is a multicentric retrospective translational study aimed at identifying distinctive molecular patterns of the I-TME with a prognostic and predictive role in mRCC (primary objective). Pretreated mRCC patients receiving ≥2nd line nivolumab have been divided according to clinical benefit in responders (PFS ≥ 12 months) versus non-responders (PFS ≤ 3 months). Secondary objectives include the correlation between primary tumor and metastases to identify a potential inter-tumor heterogeneity and the correlation with survival and response outcomes. Histological samples of primary tumors and/or metastases have been collected for the transcriptomic analyses together with clinical data of patients from medical records. The transcriptomic characterization of the I-TME of the primary tumor and/or metastases will be performed using the analytical platform "nCounter" of NanoString®, which analyzes the expression of 71 genes involved in angiogenesis, immunomodulation mediated by T-effector response, mechanisms of tumor invasion and mechanisms of calcium channel flows. The gene-panel include a group of 66 genes previously demonstrated to be related in the immune-response in mRCC (doi: 10.1038/s41598-020-58804-y) and 5 housekeeping genes (RPS13, PPIA, RPL27, RP2, B-ACT).