Treatment Of Solid Malignancies Research Articles

Impact of household income on survival in solid malignancies with synchronous brain metastases: A population-based study.

142 Background: Solid malignancies presenting with brain metastasis at the initial diagnosis usually carry a poor prognosis. Increased incidence of brain metastasis can be attributed to the advancements in neuroimaging techniques and improvements in the treatment of solid malignancies. The role of socioeconomic factors in cancer survival is being increasingly recognized. In this study, we analyzed the effect of median household income on survival outcomes in patients diagnosed with brain metastasis at the time of diagnosis of primary malignancies from 2010 to 2020. Methods: We analyzed the Surveillance, Epidemiology, and End Results (SEER) Program 17 registry (November 2022 submission) database for four primary sites of cancers based on their high propensity to develop brain metastases- Lung and/or Bronchus, Breast, Kidney and/or Renal Pelvis, and Melanoma. Patients with a median household income (MHHI) greater than 75,000 per year were classified as a high-income group, whereas those less than 75,000 per year were low-income. Patients diagnosed with malignancy during autopsy or via death certificate and with incomplete data were excluded. Kaplan-Meier method was used for 2-year survival rates and overall survival analyses. Cox regression analysis was used to calculate hazard ratios (HR). Results: A total of 66493 patients were identified across the four primary sites of tumors. Lung and/or bronchus tumors comprised most of the cases (n = 58,324). 25337 patients were in the high-income group, and 41156 patients comprised the low-income group. Median survival in the low-income group was 4 months, and in the high-income group was 5 months, with a 2-year survival rate of 11% and 18% respectively. Patients in the high-income group had better survival outcomes than the low-income [HR:0.88, 95% CI:0.86-0.90, p<0.001]. Additionally, the high-income group had 19% higher odds of receiving chemotherapy [OR:1.19, 95% CI:1.16-1.23, p<0.0001]. Amongst the cancer subgroups, household income did not have a significant effect on survival in patients with kidney and/or renal pelvis tumors [HR:0.97, 95% CI:0.88-1.06, p=0.5]. The 2-year survival rates are outlined (Table). Conclusions: Our analysis highlights a modest improvement in survival in the patient population with higher median household income. This difference could be attributed to the greater accessibility to treatment modalities and other resources for patients with higher household incomes. Further studies are needed to address socioeconomic disparities in survival for patients with solid malignancies having synchronous brain metastases. 2-year survival rates (95% CI). Cancer Groups Low-income High-income Combined Cancers 11% (11-12%) 18% (18-19%) Lung and/or Bronchus 10% (10-11%) 17% (17-18%) Breast 27% (25-29%) 34% (31-37%) Melanoma 19% (17-21%) 23% (20-25%) Kidney and/or Renal Pelvis 15% (13-17%) 18% (15-21%)

Trends in survival in solid malignancies with synchronous brain metastases: A population-based study.

e23299 Background: Brain metastasis in solid malignancies at diagnosis has a poor prognosis. Improvements in the treatment of solid malignancies and advancements in neuroimaging techniques have led to increased incidence of brain metastases. In our study, we examined survival outcomes in patients diagnosed with brain metastasis at the time of diagnosis of primary malignancy at four different sites in the year groups 2010 to 2014 and 2015 to 2020. Methods: Surveillance, Epidemiology, and End Results (SEER) Program 17 registry (November 2022 submission) database was analyzed for four primary sites of cancer based on their high propensity to develop brain metastases- lung and/or bronchus, breast, kidney and/or renal pelvis, and melanoma. Patients diagnosed with malignancy during autopsy or via death certificate and patients with incomplete survival data were excluded. R 4.3.1 software was used for all the analyses. Kaplan-Meier method was used for 2-year survival rate and overall survival analyses. Cox regression analysis was used for hazard ratios (HR). Results: A total of 29,056 and 37,437 cases were identified across the four cancer groups during the period 2010-2014 (Group 1) and 2015-2020 (Group 2), respectively. Lung and/or bronchus tumors comprised the majority of the cases (n = 58,324). 14,811 patients in Group 1 and 18,703 patients in Group 2 received chemotherapy. 8,741 patients in Group 1 and 12,533 patients in Group 2 received radiotherapy. In all the cancers combined, the median survival time in Group 1 was 4 months, and in Group 2 was 5 months. Patients in Group 2 had significantly better survival outcomes than Group 1 (HR:0.81, 95% CI:0.78-0.83, p < 0.001). Table 1 outlines the 2-year survival rates with overall survival p-value. Conclusions: Modest improvement in survival was found in patients diagnosed with synchronous brain metastases during 2015-2020 compared to patients diagnosed in 2010-2014. This slight improvement could be attributed to the improved systemic therapies for cancer, like immunotherapy, as well as advanced local therapy options for brain metastases, although the data for immunotherapy use is unavailable in the SEER database. Overall, the prognosis of synchronous brain metastases remains poor in both groups. Further studies and brain metastases inclusive clinical trials are warranted to improve outcomes in this population. [Table: see text]

RUNX2 transcriptional activity is required for CD26high CD4+ T cell development

Abstract Adoptive T cell therapy (ACT) is rapidly growing as a promising treatment option for patients who relapse or fail to respond to immunotherapy. However, in the treatment of solid tumors with ACT, many therapies fail to maintain long-term durability. We posit that CD4+ T cells expressing high levels of CD26 (CD26high T cells) would be a potent ACT product. We previously reported that they express an array of chemokine receptors, dynamic cytokine profile and regressed tumors better than other T helper subsets. Here, we developed novel cytokine priming strategies to enrich CD26high T cells from the blood of healthy donors and cancer patients. We identified a unique suite of transcription factors, including RUNX2, that are elevated on CD26high T cells. We also discovered that CD26high T cells overexpress a distinct patterns of cytokine receptor including IL-2Ra, IL-7R, IL-18R and IL-12Rβ1. Targeting these receptors via recombinant cytokine priming strategies resulted in three-to-five-fold expansion of CD26high T cells from bulk or Naive CD4+ T cells. Inhibiting RUNX2 DNA binding via small molecule inhibitors CADD522 and DIPQUO resulted significant reduction in development of CD26high CD4 T cells and decreased their cytokine production. These data suggest that RUNX2 may regulate the development and function of CD26high CD4 T cells. Taken together, these results provide evidence for the use of CD26high CD4 T cells in the treatment of solid malignancies with ACT.

New strategies for solid tumor immunotherapy based on NK cells

A major issue in treatment of solid malignancies is associated with multiplicity and rapid adaptation of immunosuppressive effects exerted by immune cells reprogrammed by the tumor. Tumor-associated macrophages (TAM), neutrophils, and tumor-infiltrating lymphocytes lose their ability to protect healthy tissues and to destroy malignant cells by activating a number of tools causing blockage of immune surveillance and reduction of therapeutic effects. Immune cells attracted by chemokines and reprogrammed by the tumor supply the malignant cells with missing nutrients (e.g., by producing arginase), support the survival of de novo recruited cells at low pH (acidosis) around malignant tissues, produce increased amounts of angiogenic factors thus contributing to increased blood supply to the tumor. Productive inflammation, being among the main types of immune response, destroys tumor pathogens and moves into chronic inflammation with progression of the tumor, thus causing immune suppression. Restoration of inflammatory immune reactions after tumor resection, chemotherapy, and radiotherapy is necessary to achieve remission without relapse or, at least, increases the time period until next episode of the disease progression. Transplantation of NK cells has a number of advantages over T lymphocytes in order of restored productive inflammation. However, it also requires additional therapeutic impacts, since various mechanisms of tumor immune escape block anti-tumor immunity. To achieve a pronounced therapeutic effect, the optimal ratio is important between the activity and number of NK cells, supporting therapeutic agents, with regard of aggressiveness and spread of malignant tumor. Among the developing areas of NK cells support, one may consider the NK cell “enhancers” (NKCE), engineered proteins that make cell therapy more selective and targeted. NKCE may activate the targeted migration of NK cells, along with blockage of inhibitory ligands. Currently, the blockage of inhibitory signals is studied in order to control metastatic tumors via KIR, NKG2A, TIGIT, TIM-3, EGFR, PD1 receptors, PDL1 and NKG2D ligand, as reported in a number of clinical and preclinical trials. The increased specificity of therapy is also achieved by usage of new-generation antibodies – nanoantibodies, aimed for targeted blocking of tumor-derived exosomes (TDE), as well as protein domains that enhance targeted migration of NK cells and therapeutic nanoparticles.

Application of CAR-T cell therapy in the treatment of liver cancer

Liver cancer is a frequent malignant tumor with a high fatality rate. However, due to the challenges of early detection and the potentially significant dangers and side effects connected with conventional cancer therapy approaches. Immunotherapy has been a well-liked cancer treatment in recent years due to its efficacy and safety. One of these is chimeric antigen receptor T cells (CAR-T), genetically modified T lymphocytes that recognize and activate T lymphocytes in response to antigens specific to tumors. They aid in the elimination of tumors. Its therapeutic efficacy in the treatment of solid malignancies is currently the subject of extensive research. Despite reaching its fifth generation, CAR-T cell therapy still faces a number of challenges when treating solid malignancies like liver cancer. As a result, this article begins with describing the creation and workings of CAR-T cells. The function it plays in treating liver cancer, including pursuing several ethical goals, was then highlighted. Future treatments for liver cancer and potentially other solid tumors can use this as a benchmark.

Postoperative Changes in Systemic Immune Tolerance Following Major Oncologic versus Minor Maxillofacial Surgery.

There is increasing evidence of the benefits of adjuvant and neoadjuvant immunotherapy in the treatment of solid malignancies like oral squamous cell carcinoma (OSCC). To optimize (neo-)adjuvant treatment, the systemic immunomodulatory effects of tumor surgery itself need to be considered. Currently, there is little evidence on the immunological effects of major surgery, such as free microvascular flap reconstruction. The current study aims to analyze how and to what extent maxillofacial surgery affects systemic parameters of immune tolerance. A total of 50 peripheral whole blood samples from patients (Group 1 (G1) = extensive OSCC surgery; Group 2 (G2) = free flap reconstruction without persistent malignant disease; Group 3 (G3) = minor maxillofacial surgery) undergoing surgery were included for real-time quantitative polymerase chain reaction (RT-qPCR) to examine changes in mRNA expression of the biomarkers IL-6, IL-10, FOXP3, and PD-L1. Blood samples were taken immediately before and after surgery as well as on the second, fourth, and tenth postoperative days. Differences in mRNA expression between groups and time points were calculated using statistical tests, including Mann-Whitney U-test and Pearson correlation analysis. Comparing postoperative expression of G1 and G3, there was a significantly higher PD-L1 expression (p = 0.015) in G1 compared to G3 and a significantly lower IL-6 (p = 0.001) and FOXP3 (p = 0.016) expression. Interestingly, IL-10 expression was higher pre- (0.05) and postoperative (p < 0.001) in G1 compared to G3. Additionally, in G1, there was a significant overexpression of IL-10 post-surgery compared to the preoperative value (p = 0.03) and a downregulated expression of FOXP3 between pre- and 2 d post-surgery (p = 0.04). Furthermore, there was a significant correlation between the duration of surgery and the perioperative expression changes of the analyzed biomarkers. As the duration of surgery increased, the expression of IL-10 and PD-L1 increased, and the expression of IL-6 and FOXP3 decreased. Extensive surgery in OSCC patients is associated with a transient shift toward postoperative systemic immune tolerance compared with patients undergoing minor surgery. However, even extensive surgery causes no signs of long-lasting systemic immunosuppression. The degree of immune tolerance that occurred was associated with the duration of surgery. This supports efforts to minimize the duration of surgery.

Sinapic acid and 3,3′-diindolylmethane potentiate cyclophosphamide antitumor activity through induction of apoptosis and inhibition of metastasis

New therapeutic strategies are required to enhance the anticancer efficacy of chemotherapeutic drugs and to reduce their cytotoxicity. The purpose of this study was to assess the anti-tumor, antimetastatic and anti-apoptotic activities of sinapic acid (SA) and 3,3'-diindolylmethane (DIM) in solid Ehrlich carcinoma (SEC) induced in mice and combining SA or DIM compounds with cyclophosphamide (CYP). For induction of solid tumor, the right hind limbs of mice were inoculated subcutaneously with Ehrlich carcinoma cells. After 5days of tumor inoculation, mice were treated with SA (56mg/kg), DIM (40mg/kg), CYP (10mg/kg), and their combinations (SA/CYP) and (SA/DIM) for 21days. The mRNA levels of Elabela, Serpina3, caspase-3, MMP-2 and MMP-9 were assessed by qPCR. Tumor and liver tissues were stained with hematoxylin and eosin for histological examination. Serum was investigated for ALT and AST activities. Treatment of SEC mice with SA and DIM significantly reduced solid tumor weight by 45.6% and 33.2%, respectively. They also reduced tumor size and increased life span of SEC mice. SA and DIM diminished area of metastatic nodules of tumor cells in the liver by 54.1% and 47.4%, respectively. They also reduced serum aminotransferases activities. Both SA and DIM were found to upregulate caspase 3 and downregulate MMP-2 and MMP-9. Furthermore, SA and DIM reduced gene expression of Elabela by (44.8% and 35.1%) and Serpina3 by (30.7% and 23.5%), respectively. SA and DIM were also shown to potentiate the anti-tumor activity CYP. SA and DIM showed promising antitumor effects and enhanced CYP antitumor activity mostly through upregulation of apoptotic caspase 3 and suppressing metastatic enzymes MMP-2 and MMP-9. Additionally, SA and DIM exhibited a hepatoprotective effect. Our results suggest that these natural compounds may be used to improve the efficacy and reduce the adverse effects of chemotherapeutic drugs in the treatment of solid malignancies.

Controlled 5‐FU Release from P(NIPAM‐co‐VIm)‐g‐PEG Dual Responsive Hydrogels

Abstract5‐fluorouracil (5‐FU) forms the basis of many chemotherapy regimens and is one of the most widely used chemotherapeutic drugs in the treatment of solid malignancies. In this study, (i) Poly N‐isopropyl acrylamide (PNIPAM) synthesized by free radical polymerization method, (ii) temperature and pH responsive P(NIPAM‐co‐VIm) synthesized by copolymerization of N‐isopropyl acrylamide (NIPAM) with 1‐vinyl imidazole (VIm) and (iii) the 5‐FU release of P(NIPAM‐co‐VIm)‐g‐PEG prepared by grafting with polyethylene glycol (PEG). In the temperature and pH sensitivity analyzes revelaed that the LCST value increased as a result of the treatment of PNIPAM with VIm and PEG, on the other hand the hydrogel in the swollen phase in the acidic environment, the hydrogel turned into a precipitated form as the environment became alkaline. To investigate the utilize of hydrogels, release mediums of two different pHs (pH 5.5 and 7.4) and two different temperatures (25 °C and 37 °C) were applied. The cumulative release results showed that the release ratio of 5‐FU was 95 % when the release medium pH was 7.4 and ambient temperature 37 °C. Consequently, P(NIPAM‐co‐VIm)‐g‐PEG hydrogels at different pH and temperature mediums could be beneficially utilized as an material with a potential to be used in targeted drug delivery systems.

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

The Emergence of Cancer Stem Cells in Early Diagnosed Prostate Cancer

Protective effect of rosmarinic acid on the transmembrane transporter Ctr1 expression in cisplatin-treated mice.

Cisplatin (cis-diamminedichloroplatinum(II), CP) is a platinum-based anticancer drug widely used in the treatment of solid malignancies. However, its side effects, particularly nephrotoxicity, are limiting factors in its clinic use. Rosmarinic acid (RA), a natural antioxidant compound, is reported to attenuate oxidative stress and associated pathophysiological outcomes. Our study aimed to explore the protective effect of RA against CP-induced acute kidney injury (AKI). We investigated the effect of RA at the dose of 100 mg/kg on AKI induced by CP (20 mg/kg) in mice. Various parameters of nephrotoxicity such as levels of serum electrolytes, albumin, and globulin were measured using standardized methods. Besides, a specific biomarker of damage to proximal tubular cells, kidney injury molecule-1 (Kim-1), was measured in the serum by ELISA. mRNA expression of Kim-1 and a transmembrane transporter, copper transporter 1 (Ctr1), was analyzed by quantitative reverse transcriptase-polymerase chain reaction. CTR1 expression was also analyzed by western blot technique. RA treatment restored the downregulated CTR1 , a renal transmembrane transporter in CP-treated mice. It was accompanied by a reduction in the level of serum albumin and globulin. Serum electrolytes such as Na+, K+, and Ca2+ in CP-treated mice were found to be restored with RA treatment. Moreover, RA also significantly downregulated the increased expression of nephrotoxicity biomarker KIM-1. Overall, RA proved to be an effective nephroprotective compound which afforded protection at cellular and subcellular levels with an appreciable modulatory effect on a transmembrane transporter.

Single-cell RNA-Seq reveals the potential risk of anti-mesothelin CAR T Cell therapy toxicity to different organs in humans.

“On-target off-tumor” toxicity is a major challenge to the use of chimeric antigen receptor (CAR)-engineered T cells in the treatment of solid malignancies, because of the expression of target antigens in normal tissues. Mesothelin overexpression is associated with poor prognosis of multiple solid tumors, and would therefore appear to be a suitable antigen target. To understand the risk of toxicity to different organs on anti-mesothelin CAR T cell therapy, single-cell RNA sequencing (scRNA-seq) datasets derived from major human physiological systems were analyzed in this study, including the respiratory, cardiovascular, digestive, and urinary systems. According to scRNA-seq datasets, the organs were stratified into high or low risk based on the level of mesothelin expression. We report that the proportion of mesothelin-positive cells was 7.71%, 2.40% and 2.20% of myocardial cells, pulmonary cells and stomach cells, respectively, indicating that these organs could be at high risk of “on-target off-tumor” toxicity on anti-mesothelin CAR T cell therapy. By contrast, esophagus, ileum, liver, kidney and bladder exhibited low mesothelin expression (<1%). Therefore, these organs could be regarded as at low risk. Thus, the risk of toxicity to different organs and tissues in anti-mesothelin CAR T cell therapy may be predicted by these scRNA-seq data.

Abstract LB220: The anticalin-antibody bispecific PRS-352/S095025 strongly stimulates human CD4+ T cells in a PD-L1-dependent manner

Abstract Background: OX40, a member of the tumor necrosis factor receptor superfamily, is a costimulatory molecule promoting survival and cytokine release by effector T cells and inhibiting human regulatory T-cell activity. OX40 activation has been explored as a potential treatment for solid malignancies, using mainly agonistic anti-OX40 antibodies. These antibodies rely on Fc gamma receptor (FcγR)-mediated crosslinking to activate the OX40 pathway and have shown so far only limited antitumoral efficacy in clinical settings. One underlying hypothesis is that FcγR crosslinking of these antibodies may not allow optimal activation of the OX40 pathway to fully exploit the potential of this target for immunotherapy of cancer. To overcome this limitation, we designed PRS-352/S095025, a strong PD-L1-dependent OX40 agonistic bispecific molecule, that allows combination of OX40 costimulation and PD-L1 blockade. Methods: We generated an Anticalin protein that binds with high affinity to human OX40. Anticalin® proteins are approximately 18-20 kDa protein therapeutics derived from human lipocalins that can be engineered to bind with high affinity and specificity to different targets. The PRS-352/S095025 bispecific fusion protein was obtained by genetic fusion of OX40-targeting Anticalin protein to a PD-L1-targeting monoclonal antibody with a modified IgG4 backbone, allowing an optimal activation of OX40 in the presence of PD-L1, but not FcγRs. Results: We showed that PRS-352/S095025 retains binding to PD-L1 like the anti PD-L1 antibody backbone alone and binds with high affinity to both human and cynomolgus OX40. We showed that PRS-352/S095025 inhibited the PD-1/PD-L1 pathway, as the parental PD-L1 targeting antibody and an approved anti PD-L1 antibody. In addition to its PD-L1 blocking properties, we showed that PRS-352/S095025 activates OX40, and that this activity is dependent on the expression of PD-L1 and not on FcγR, consistent with the desired mechanism of action. Furthermore, we demonstrated that PRS-352/S095025 activity is superior to both PD-L1 benchmark antibodies and to the combination of clinically relevant OX40 and PD-L1 benchmark antibodies. We could also show that PRS352/S095025 strongly stimulated human CD4 T cells. In vivo, we showed that PRS-352/S095025 has a PK profile similar to that of the PD-L1 antibody alone. Conclusions: We provide here the preclinical characterization of the fusion protein PRS-352/S095025, a bispecific molecule composed of a PD-L1 blocking moiety and an Anticalin protein agonizing OX40. In vitro, this molecule showed the desired MoA, PD-L1 blocking and potent OX40 agonism driven by binding to PD-L1, with superior activity to a clinical stage OX40 agonist. Citation Format: Lucia Pattarini, Marina Pavlidou, Aizea Kastresana Morales, Janet Peper-Gabriel, Matthieu Riviere, Didier Demarles, Alix Scholer-Dahirel, Veronique Blanc, Shane Olwill. The anticalin-antibody bispecific PRS-352/S095025 strongly stimulates human CD4+ T cells in a PD-L1-dependent manner [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB220.

Development of a predictive model for emergency room utilization and unanticipated hospital admission in patients receiving cancer treatment for solid tumor malignancies.

e18674 Background: Unanticipated healthcare resource utilization, in the form of either emergency department utilization (EDUs) or hospital admission (HA), is an indicator of lower quality of cancer care. The objective of this study was to develop a comprehensive predictive model for emergency department utilization and hospital admission (HA) for patients with solid tumors who received chemotherapy within 30 days. Methods: We abstracted electronic health data on oncology encounters from all patients receiving systemic therapy chemotherapy for solid tumors from March 01, 2015 to August 21, 2020. Patients included in the cohort met the following criteria:1) Ages &gt; = 18 years old 2) Diagnosed with any solid tumor (3) Had any oncology treatment plan related to their solid tumor diagnosis; 4) Received at least one chemotherapy during March 01, 2015 through August 21, 2020. We defined a primary composite outcome of emergency visit or unanticipated hospitalization within 30 days after the encounter. Patient information was abstracted. We developed a predictive model for the primary outcome using LASSO logistic regression modeling. To evaluate the model, we calculated the Area Under the Receiver Operator Characteristic (AUROC) and the calibration slope. Results: 12,917 unique patients with 134,641 encounters were included. Of these, 9100 (6.7%) of encounters were ED visits or hospitalizations. 714 patients (5.5%) had at least one ED visit or hospitalization within 30 days of treatment; patients at highest risk for this outcome included those with pancreatic cancer, lung cancer and ovarian/endometrial cancer (9.1%, 7.4% and 6.8% respectively). 38 variables were identified as contributing to the LASSO model. The top predictors, in order of importance, were fever, hypernatremia, hypotension and low albumin. The model’s AUC was 0.83, indicating good model sensitivity to outcome. Conclusions: Approximately 7% of healthcare encounters in patients undergoing treatment for solid malignancies were ED visits or hospitalizations. Identifying patients at highest risk for this outcome may prevent unnecessary resource utilization and optimize patient care during cancer treatment. The model developed in this study demonstrated good sensitivity and could be implemented in clinical practice to allow for preventive outpatient interventions. Work is ongoing to integrate this model into clinical care at our institution.[Table: see text]

CORONARY VASOSPASM ASSOCIATED WITH 5-FLUOROURACIL CHEMOTHERAPY

SESSION TITLE: Medical Student/Resident Cardiovascular Disease Posters SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: 5-Fluorouracil (5FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies, particularly colorectal and pancreatic neoplasms. (1,2) Coronary vasospasm associated with 5FU is a known complication. (3) Cardiotoxicity occurs in 1% to 18% of patients receiving 5FU, and the incidence of this complication is on the rise.(4) The objective of this report is to highlight the characteristics of this uncommon complication. CASE PRESENTATION: A 66-year-old male with a past medical history of coronary artery disease status-post 4-vessel coronary artery bypass graft surgery and stage 4 colon adenocarcinoma with metastasis to the liver, presented to the emergency department (ED) with complaints of sudden onset of burning deep sub-sternal chest pain with no radiation. The chest pain began approximately eight hours after his first round of 5FU, leuocorin and eloxatin (FOLFOX) chemotherapy. In the ED he was given aspirin and heparin. EKG was concerning for ST-segment elevation myocardial infarction in the inferior leads. Troponins were negative (<0.01). A subsequent left heart catheterization revealed patent grafts and normal coronary arteries. An echocardiogram showed no acute wall motion abnormalities and an ejection fraction of 65%. The 5FU was discontinued and the patient’s chest pain improved. He was discharged with sublingual nitroglycerin and diltiazem. Two weeks later, the patient returned with similar chest pain after his second cycle with 5FU, leuocorin and eloxatin (FOLFOX). The symptoms of his coronary artery vasospasm were believed to be due to 5FU chemotherapy. He was further instructed to go to the cardiovascular ICU to receive nitroglycerine infusions before each cycle of FOLFOX. Unfortunately, the patient expired two months after starting chemotherapy; from cardiopulmonary arrest secondary to sepsis. DISCUSSION: This is a case of a 66-year-old male with a past medical history of coronary artery disease and stage 4 colon adenocarcinoma on 5-Fluorouracil, leuocorin and eloxatin (FOLFOX) chemotherapy presenting for coronary vasospasm likely from 5-Fluorouracil. Cardiotoxicity related to 5FU is poorly understood. Leading theories of the mechanism of 5FU-induced coronary vasospasm seem to involve 5FU's modification of smooth muscle tone. (5,6) Patients on 5FU with coronary vasospasm may have ECG findings suggestive of occlusion, (3) similar to our patient. Treatment of affected patients is determined by confirmation of 5FU as the definitive cause of the coronary vasospasm, as well as the requirement of 5FU as the only suitable chemotherapeutic agent. If possible, care providers should consider switching to an acceptable chemotherapeutic substitute. CONCLUSIONS: In conclusion, consideration should be given for patients with coronary artery disease starting 5-Fluorouracil chemotherapy. Reference #1: 1. Grem JL. 5-Fluorouracil: forty-plus and still ticking. A review of its preclinical and clinical development. Invest New Drugs 2000; 18: 299-313. 2. Myers CE. The pharmacology of the fluoropyrimidines. Pharmacol Rev 1981; 33: 1-15. 3. de Forni M, Malet-Martino MC, Jailais P, et al. Cardiotoxicity of high-dose continuous infusion fluorouracil: a prospective clinical study. Clin Oncol 1992; 10: 1795-1801. 4. Lestuzzi C, Vaccher E, Talamini R, et al. Effort myocardial ischemia during chemotherapy with 5-fluorouracil: an underestimated risk. Ann Oncol 2014; 25: 1059-1064. 5. Bonetti PO, Lerman LO and Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. Arterioscler Throb Vasc Biol 2003, 23: 168-175. 6. Reddy KG, Nair RN, Sheehan HM, et al. Evidence that selective endothelial dysfunction may occur in the absence of angiographic or ultrasound atherosclerosis in patients with risk factors for artherosclerosis. I Am Coll Cardio! 1994; 23: 833-843. DISCLOSURES: No relevant relationships by Ahmad ababneh, source=Web Response No relevant relationships by HANAD BASHIR, source=Web Response No relevant relationships by Ahmad JABRI, source=Web Response No relevant relationships by Gauranga Mahalwar, source=Web Response

Abstract 666: A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry

Abstract The inhibition of PI3Kδ preferentially targets regulatory T cells and myeloid derived suppressor cells, breaking tumour-induced immune tolerance and restoring anti-tumour immunity. Bioinformatics and protein expression studies have shown that PIK3CD/PI3Kδ is also highly expressed in certain solid malignancies. IOA-244 is a novel, highly selective PI3Kδ inhibitor, with the unique property of being ATP non-competitive. In addition to the effects of PI3Kδ inhibition on the balance of CD8+ T cells and T regulatory cells in the tumour microenvironment, we have recently demonstrated that IOA-244 effectively controls the growth of tumour cells with high levels of PI3Kδ in vivo in T-cell deficient hosts. Analysis of TCGA datasets shows that certain solid tumours express high levels of PIK3CD transcript, comparable to that of diffuse large B cell lymphoma. Of these indications, cutaneous and uveal melanoma are amongst the highest expressers. To support the clinical development of IOA-244, we demonstrate that patient-derived melanoma cells with a high expression of PIK3CD are susceptible to treatment with IOA-244 in a mouse patient-derived xenograft model. Furthermore, in vitro explant studies using clinical biopsy material demonstrates that PI3Kδ expression can be detected in tumour tissue and that IOA-244 has an anti-proliferative function when added to these samples. Based on these and other supporting data, IOA-244 has received clinical trial approval in Europe and phase I clinical testing is underway in solid tumours with an anticipated high Treg:CD8 ratio and/or high protein expression of PI3Kδ. Citation Format: Amy R. MacQueen, Giuditta Viticchie, Karolina Niewola, Francesca Finotello, Ian Powley, Pritom Shah, Lars van der Veen, Michael Lahn, Zoe Johnson. A novel, highly selective PI3Kδ inhibitor for the treatment of solid malignancies that express high levels of target protein as assessed by immunohistochemistry [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 666.

Use of Anticancer Platinum Compounds in Combination Therapies and Challenges in Drug Delivery.

As one of the leading and most important metal-based drugs, platinum-based pharmaceuticals are widely used in the treatment of solid malignancies. Despite significant side effects and acquired drug resistance have limited their clinical applications, platinum has shown strong inhibitory effects for a wide assortment of tumors. Drug delivery systems using emerging technologies such as liposomes, dendrimers, polymers, nanotubes and other nanocompositions, all show promise for the safe delivery of platinum-based compounds. Due to the specificity of nano-formulations; unwanted side-effects and drug resistance can be largely averted. In addition, combinational therapy has been shown to be an effective way to improve the efficacy of platinum based anti-tumor drugs. This review first introduces drug delivery systems used for platinum and combinational therapeutic delivery. Then we highlight some of the recent advances in the field of drug delivery for combinational therapy; specifically progress in leveraging the cytotoxic nature of platinum-based drugs, the combinational effect of other drugs with platinum, while evaluating the drug targeting, side effect reducing and sitespecific nature of nanotechnology-based delivery platforms.

SAT-039 The Short-Term Effect of Multiple Kinase Inhibitor (Lenvatinib) on Spermatogenesis in Mice

Lenvatinib, a multi-kinase inhibitor, is used in the treatment of solid malignancies. Lenvatinib belongs to a family of tyrosine kinase inhibitors and targets VEGF receptors 1-3, FGF receptors 1-4, PDGF receptor alpha, RET and KIT. However, it is not known whether Lenvatinib like other chemotherapeutic drugs affects spermatogenesis. The objective of this study was to examine whether Lenvatinib induces damage to spermatogenesis in mice. Twenty adult mice (C57BL/6) were randomly divided into 2 groups to receive daily gavage of either water (as control) or Lenvatinib (10 mg/kg) for 6 weeks. All mice were euthanized at the end of the study. We identified that Lenvatinib significantly (p<0.05) decreased testis weight (TW: 91.75±1.49mg) compared to control mice (TW: 111.9±3.07mg). This difference in testis weight however, became non-significant after correcting for body weight. The cauda epididymal sperm count was significantly (p<0.01) decreased in the Lenvatinib treated (0.82±0.04 million/mg cauda) as compared to control (1.26±0.07 million/mg cauda) mice. There were no differences in plasma testosterone concentrations between Lenvatinib treated (29.76±7.67ng/dl) and control (31.72±6.89ng/dl) mice. Lenvatinib did not induce notable morphological changes in testicular histology. We conclude that 6 weeks of Lenvatinib treatment had minimal effect if any on mouse spermatogenesis. The long-term treatment effect of Lenvatinib on spermatogenesis remains to be determined.

IL7-IL12 Engineered Mesenchymal Stem Cells (MSCs) Improve A CAR T Cell Attack Against Colorectal Cancer Cells.

Chimeric antigen receptor (CAR) redirected T cells are efficacious in the treatment of leukemia/lymphoma, however, showed less capacities in eliminating solid tumors which is thought to be partly due to the lack of cytokine support in the tumor lesion. In order to deliver supportive cytokines, we took advantage of the inherent ability of mesenchymal stem cells (MSCs) to actively migrate to tumor sites and engineered MSCs to release both IL7 and IL12 to promote homeostatic expansion and Th1 polarization. There is a mutual interaction between engineered MSCs and CAR T cells; in presence of CAR T cell released IFN-γ and TNF-α, chronic inflammatory Th2 MSCs shifted towards a Th17/Th1 pattern with IL2 and IL15 release that mutually activated CAR T cells with extended persistence, amplification, killing and protection from activation induced cell death. MSCs releasing IL7 and IL12 were superior over non-modified MSCs in supporting the CAR T cell response and improved the anti-tumor attack in a transplant tumor model. Data demonstrate the first use of genetically modified MSCs as vehicles to deliver immuno-modulatory proteins to the tumor tissue in order to improve the efficacy of CAR T cells in the treatment of solid malignancies.

VENTRICULAR FIBRILLATION AND MYOCARDITIS SECONDARY TO 5-FLUOROURACIL

5-fluorouracil (5-FU) is a potent chemotherapeutic agent in the fluoropyrimidine class and is widely used in the treatment of solid malignancies. It is associated with cardiotoxicity, with known complications including acute MI, heart failure, or arrhythmia. A 28-year-old male with metastatic colon

259Higher risk of myocardial infarction in the first year following 5-fluorouracil treatment

Abstract Abstract Background 5-fluorouracil (5-FU) is the third most commonly used chemotherapeutic agent in the treatment of solid malignancies across the world. The most common manifestation of cardiotoxicity associated with 5-FU is chest pain, presenting as atypical chest pain, angina on exertion or rest and acute coronary syndromes including myocardial infarction and in worse case even death. Nevertheless, a widespread appreciation of 5-FU related cardiotoxicity including myocardial infarction is poorly understood. Purpose This study aims to examine risk of myocardial infarction in patients treated with 5-FU compared to age- and sex-matched population controls. Methods and results Methods: Individuals treated with 5-FU between 2004 and 2014 in the Danish National Patient Register were identified and risk set matching was used to find background population controls matched on age and sex in a 1:5 ratio. Furthermore, two years follow-up time were added with total 13 years. Neither 5-FU patients nor controls had prior ischemic disease. Aalen-Johansen and Kaplan-Meier estimates were used to report the cumulative incidence of myocardial infarction and all-cause mortality, respectively. A multivariable Shared Frailty Cox regression analysis (adjusted for patient age, sex, hypertension, hypercholesterolemia, diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation as well as selected anti-anginal medications including nitrates, beta- and calcium-blockers) was used to determine the association between 5-FU treatment and the one-year risk of myocardial infarction. Results A total of 9,012 5-FU patients and 45,060 controls formed the study population. Differences in comorbid conditions (diabetes, chronic obstructive pulmonary disease, chronic kidney disease, heart failure and atrial fibrillation) and selected anti-anginal medications (nitrates, beta- and calcium-blockers) were non-significant (all P&gt;0.05). The one-year cumulative incidence of myocardial infarction is significantly higher for 5-FU patients at 0.8% versus 0.6% among population controls (Figure 1A), with a competing risk of death of 25.1% versus 1.2%. The risk diminishes beyond one year and becomes lower for 5-FU patients with time (Figure 1A), along with an increasing all-cause mortality (Figure 1B). The unadjusted and adjusted hazard ratio for the one-year risk of myocardial infarction were 1.38 [95% CI 1.07–1.78] and 1.54 [95% CI 1.19–1.99]. Conclusions Although the one-year risk of myocardial infarction is higher among 5-FU patients compared with population controls, the absolute risk is small and becomes insignificant beyond one year of follow-up.