Current Standard Of Care Therapy Research Articles

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC)

BackgroundTherapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking.MethodsTrans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses.DiscussionThe SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research.Trial registrationanzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective

Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM—namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity.

Review of CAR T-Cell Therapy in Multiple Myeloma: A Canadian Perspective

Multiple myeloma (MM) is an incurable plasma cell malignancy. In the context of the current standard of care therapies in Canada, outcomes among patients with relapsed/refractory multiple myeloma (RRMM), particularly those with triple-class (or more) refractory disease remain poor. Immunotherapies have significantly changed the treatment landscape of MM. Since 2021, two BCMA-targeting CAR T-cell therapy products have been approved for RRMM—namely Idecabtagene vicleucel (Ide-cel) (ABECMA®) and Ciltacabtagene autoleucel (Cilta-cel) (CARVYKTI®), both of which are available in the US and Europe. Although they have shown unprecedented efficacy in RRMM, their clinical and logistical limitations must be acknowledged. MM CAR T-cell therapy is likely to be approved in Canada soon. Therefore, it is timely that we review the latest evidence for commercially available CAR T-cell therapy in multiple myeloma, with a focus on its relevance and impact in the Canadian setting. There will be challenges to access and strategies must be in place to ensure equitable care for all Canadians with MM. Alongside haematologists working in the immune effector cell therapy programs, providers in the community will also play a role in the ongoing monitoring and management of long-term side effects including opportunistic infections and late neurotoxicity.

Current Treatment Options for Renal Cell Carcinoma: Focus on Cell-Based Immunotherapy.

Renal cell carcinoma (RCC) affects over 400,000 patients globally each year, and 30% of patients present with metastatic disease. Current standard of care therapy for metastatic RCC involve TKIs and ICIs, including combinatorial strategies, but this offers only modest clinical benefit. Novel treatment approaches are warranted, and cell-based immunotherapies for RCC hold significant promise. These are currently being tested in the pre-clinical setting and in early phase clinical trials. Here, we review the landscape of cellular immunotherapy for RCC in the context of currently available therapies, with a particular focus on defining the current best antigenic targets, the range of cell therapy products being explored in RCC, and how advanced engineering solutions may further enhance these therapies in the RCC space.

BSLD-02 ELUCIDATING LEPTOMENINGEAL MICROENVIRONMENT CUES THAT PROMOTE METASTASIS AND CHEMOTHERAPY RESISTANCE IN HIGH-RISK MEDULLOBLASTOMA

Abstract Medulloblastoma is a molecularly heterogenous brain tumor of the cerebellum and is a leading cause of pediatric cancer mortality due to its propensity for leptomeningeal metastasis. Leptomeningeal metastasis occurs in over 20-30% of patients despite age- and risk- adapted chemoradiation therapy. The mechanisms responsible for medulloblastoma metastasis and therapy resistance remain incompletely understood. The leptomeninges represent a fundamentally distinct microenvironment from the primary cerebellar tumor. We hypothesized that unique signaling inputs from the cellular and extracellular milieu of the leptomeninges drive distinct medulloblastoma biology that leads to resistance to current standard of care therapy. We tested this hypothesis using Group 3-MYC amplified (Grp3-MA) cell lines given their high metastatic potential. Primary tumors grow within a glycosaminoglycan (hyaluronan) rich matrix while leptomeningeal metastases grow in a laminar fashion attached to leptomeningeal (pial) cells that were enriched for laminins, collagens, and fibronectin. Analogously, Grp3-MA cells grow in suspension at steady state, but subpopulations readily adhere to a leptomeningeal membrane mimetic in vitro. This attachment required integrin beta 1 (ITGB1) and promoted chemotherapy resistance. We additionally have created a novel co-culture model wherein medulloblastoma cells grow as adherent clusters on a layer of primary leptomeningeal cells in an ITGB1 dependent manner. We are using this co-culture platform to perform single cell RNA sequencing and ligand receptor analysis to understand how cell-cell communication between leptomeningeal cells and medulloblastoma cells promotes tumor cell growth. Collectively, our studies demonstrate that cues from the leptomeningeal microenvironment alter medulloblastoma cell behavior and are attractive targets for developing novel therapies against metastasis.

SPinal cOrd neUromodulatioN to treat Cerebral palsy in pEdiatrics: POUNCE Multisite Randomized Clinical Trial.

Cerebral palsy (CP) affects up to 4 children in 1,000 live births, making it the most common motor disorder in children. It impairs the child's ability to move voluntarily and maintain balance and posture, and results in a wide range of other functional disorders during early development impairments in various sensory modalities, e.g., vision, hearing ability and proprioception. Current standard of care therapy focuses on symptom management and does not mitigate the progression of many of these underlying neurological impairments. The goal of this trial is to conduct a prospective multicenter, double-blinded, sham-controlled, crossover, randomized control trial to demonstrate the safety and efficacy of noninvasive spinal cord neuromodulation (SCiP™, SpineX Inc.) in conjunction with activity-based neurorehabilitation therapy (ABNT) to improve voluntary sensorimotor function in children with cerebral palsy. Sixty participants (aged 2-13 years) diagnosed with CP classified as Gross Motor Function Classification Scale Levels I-V will be recruited and divided equally into two groups (G1 and G2). Both groups will receive identical ABNT 2 days/wk. G1 will initially receive sham stimulation, whereas G2 will receive therapeutic SCiP™ therapy for 8 weeks. After 8 weeks, G1 will cross over and receive therapeutic SCiP™ therapy for 8 weeks, whereas G2 will continue to receive SCiP™ therapy for another 8 weeks, for a total of 16 weeks. Primary and secondary outcome measures will include Gross Motor Function Measure-88 and Modified Ashworth Scale, respectively. Frequency and severity of adverse events will be established by safety analyses. The trial is registered on clinicaltrials.gov (NCT05720208). The results from this trial will be reported on clinicaltrials.gov, published in peer-reviewed journals and presented at scientific and clinical conferences.

Ensifentrine as a Novel, Inhaled Treatment for Patients with COPD.

Ensifentrine is a novel, potent, and selective dual inhibitor of phosphodiesterase (PDE)3 and PDE4 designed for delivery by inhalation that combines effects on airway inflammation, bronchodilation and ciliary function in bronchial epithelia. In Phase 2 studies in subjects with COPD, ensifentrine demonstrated clinically meaningful bronchodilation and improvements in symptoms and health-related quality of life when administered alone or in combination with current standard of care therapies. Ensifentrine is currently in late-stage clinical development for the maintenance treatment of patients with COPD. This review summarizes non-clinical data as well as Phase 1 and Phase 2 efficacy and safety results of nebulized ensifentrine relevant to the maintenance treatment of patients with COPD.

Abstract 33: Epidemiology, Diagnosis, and Outcomes of Pediatric Burkitt Lymphoma Patients Treated at Bugando Medical Centre in Mwanza, Tanzania

Abstract Purpose: Despite the significant improvement in outcomes over the last few decades for the treatment of pediatric Burkitt lymphoma, outcomes in sub-Saharan Africa remain poor, with an approximately 50% survival rate. This disparity is likely multifactorial and significant work remains to improve these outcomes in low resource settings. As a first step in attempting to improve these disparate outcomes at our hospital, Bugando Medical Centre (BMC), in Mwanza, Tanzania, we aim to improve the understanding of the presentation, diagnosis, and outcomes with the current standard of care therapy at our site. We propose that a better understanding of the current nature of care for these patients at our site will allow for more informed future interventions aimed at improving outcomes. Methods: Historical patient data were abstracted for pediatric patients with a diagnosis of Burkitt lymphoma treated at BMC from 2016-2022. Patients’ initial presentations (e.g. site of disease), means of diagnosis, treatment completion rate, and outcomes (if available) were analyzed. Results: Data were available on 109 patients with a diagnosis of Burkitt lymphoma between 2016-2022. Patients were on average 7.7 years old at presentation. We observed a 2:1 male to female ratio. We observed a significant proportion of abdominal disease with 58.7% presenting with abdominal disease (either alone or in combination) at initial diagnosis. There were 91% of patients who were deemed INCTR ‘high risk’ at diagnosis. There was a notable improvement in the percent of patients diagnosed with a biopsy with 46% in 2016 and 100% in 2022. Outcomes were poor but were difficult to assess with clarity due to a high rate of abandonment. Within those limitations, we observed a 1-year overall survival, of patients through 2021 with known outcomes, of 50.2% and a 1-year event free survival of 34.1% (including abandoment as an event). Conclusion: Overall, in our patients we note epidemiology consistent with known data for endemic Burkitt lymphoma. Our patient population includes a significant proportion of abdominal and/or high-risk disease. We demonstrate overall poor outcomes with a high degree of treatment abandonment. These data suggest that improvement in treatment efficacy and treatment adherence may improve outcomes. Citation Format: Hutton Chapman, Paul S. Ntemi, Jacqueline Kamanga, Judith Paschal, Heronima J. Kashaigili, Kristin Schroeder. Epidemiology, Diagnosis, and Outcomes of Pediatric Burkitt Lymphoma Patients Treated at Bugando Medical Centre in Mwanza, Tanzania [abstract]. In: Proceedings of the 11th Annual Symposium on Global Cancer Research; Closing the Research-to-Implementation Gap; 2023 Apr 4-6. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(6_Suppl):Abstract nr 33.

Current and emerging approaches to noncompetitive AR inhibition.

The androgen receptor (AR) has been shown to be a key determinant in the pathogenesis of castration-resistant prostate cancer (CRPC). The current standard of care therapies targets the ligand-binding domain of the receptor and can afford improvements to life expectancy often only in the order of months before resistance occurs. Emerging preclinical and clinical compounds that inhibit receptor activity via differentiated mechanisms of action which are orthogonal to current antiandrogens show promise for overcoming treatment resistance. In this review, we present an authoritative summary of molecules that noncompetitively target the AR. Emerging small molecule strategies for targeting alternative domains of the AR represent a promising area of research that shows significant potential for future therapies. The overall quality of lead candidates in the area of noncompetitive AR inhibition is discussed, and it identifies the key chemotypes and associated properties which are likely to be, or are currently, positioned to be first in human applications.

Abstract CT136: An open-label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced hematological malignancies

Abstract Background Inobrodib (CCS1477) is a first in class potent, selective, and orally bioavailable inhibitor of the bromodomains of p300 and CBP, two closely related histone acetyl transferases with oncogenic roles in hematological malignancies. In pre-clinical studies inobrodib potently inhibited cell proliferation in acute myeloid leukemia (AML), multiple myeloma (MM) and non-Hodgkin lymphoma (NHL) cell lines. Inobrodib demonstrated dose-dependent efficacy in corresponding xenograft models, eliciting tumor regression at the highest doses. These effects were accompanied by significant reductions in expression of MYC, MYB and IRF4. Low doses of inobrodib also demonstrated good efficacy when added to standard-of-care treatments, providing a strong rationale for combination treatment in patients. Inobrodib represents a novel and differentiated approach and offers a potential new therapeutic option for patients who have relapsed or are refractory to current standard of care therapies in AML, higher risk MDS, MM or NHL. Study Design and Methods NCT04068597 is an adaptive multi-arm/multi-stage trial allowing exploration of p300/CBP inhibition as monotherapy or in combination with different agents across multiple indications including AML/higher risk MDS, MM, and NHL. The trial was initiated as a dose escalation rolling 6 design separately in AML/MDS and MM/NHL to ensure tolerability is explored separately across groups of indications, with the possibility to expand in monotherapy across different indications. Key inclusion criteria include patients with confirmed relapsed or refractory disease, with patients having received standard therapy (typically at least two prior lines of therapy). Response criteria are assessed using standard methodologies for the different indications. Blood and tumor samples are collected for exploratory biomarker analysis to understand mechanisms of response to treatment or disease progression. The recommended phase 2 dose/schedule has been determined, and monotherapy expansion arms are currently open in selected indications. Cohorts investigating dose escalation with standard of care agents pomalidomide/dexamethasone in MM as well azacytidine with or without venetoclax in AML or MDS are currently enrolling, with the possibility of expansion for promising combinations. An additional ‘rescue’ cohort for MM patient who failed inobrodib monotherapy will be used to determine whether addition of pomalidomide with or without dexamethasone may reverse resistance to inobrodib. This cohort will also explore tolerability and clinical activity of steroid-sparing combination regimen. Citation Format: Tomasz Knurowski, Emma Searle, Karen Clegg, Neil Pegg, William West, Debbie Haynes, Kristopher Frese, Tim C. Somervaille. An open-label phase I/IIa study to evaluate the safety and efficacy of CCS1477 as monotherapy and in combination in patients with advanced hematological malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT136.

Abstract 3396: Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM

Abstract Acquired resistance to 3rd generation EGFR inhibitors used in the treatment of NSCLC is common. While the EGFR C797S substitution is a frequently reported post-osimertinib resistance mutation, real world evidence indicates the emergence of additional EGFR alterations that can drive drug resistance: kinase domain mutations (e.g., S768I), extracellular domain alterations (e.g., EGFRvIII, A289X), and EGFR amplification. Moreover, while osimertinib targets the classical EGFR mutations, primary NSCLC tumors are also driven by other oncogenic kinase domain mutations including G719X, S768I, and L861Q, which confer de novo (intrinsic) resistance to 3rd generation EGFR TKIs. A family of extracellular domain alterations occurs in nearly 50% of GBM patients, and these alterations are clinically resistant to all current generation inhibitors. Real world data in GBM demonstrate these EGFR alterations often co-occur and persist throughout treatment with current standard of care therapy. Of critical importance is the observation that the oncogenic isoform of EGFR in GBM is a covalent homo-dimer which can be formed and paradoxically activated by the binding of reversible 1st generation EGFR inhibitors. There is a significant clinical need to develop a potent CNS penetrant EGFR inhibitor that would target both acquired and intrinsic resistance mutations expressed in NSCLC and co-occurring EGFR alterations in GBM. An effective inhibitor should meet four design principles; 1) potent and selective against a broad family of intracellular, extracellular EGFR oncogenic alterations and amplification, 2) wild type EGFR sparing, 3) irreversible to avoid paradoxical activation, and 4) CNS penetrant. BDTX-1535 is a 4th generation irreversible CNS penetrant EGFR MasterKey inhibitor targeting a family of oncogenic EGFR extracellular domain alterations and amplification in GBM patients and EGFR resistance mutations in NSCLC. BDTX-1535 meets all four criteria for a highly effective EGFR inhibitor and was designed using the MAP Discovery Engine to target the activated conformations used by oncogenic EGFR to drive tumorigenesis. BDTX-1535 achieves potent anti-tumor activity against EGFR alterations and amplification across models including NSCLC and GBM PDX and intracranial tumors. BDTX-1535 is currently in a phase I clinical study in patients with NSCLC and GBM harboring sensitive EGFR alterations (NCT05256290). Citation Format: Matthew O'Connor, Matthew Lucas, Sherri Smith, Anthony Trombino, Sudharshan Eathiraj, Elizabeth Buck. Discovery of BDTX-1535, a novel 4th generation, irreversible, potent, wild type sparing EGFR MasterKey inhibitor that targets oncogenic kinase domain mutations as well as extracellular domain alterations for the treatment of NSCLC and GBM [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3396.

Abstract 2280: BG34-200 immunotherapy of advanced melanoma

Abstract Background: High levels of myeloid derived cells are characteristic of tumor microenvironment (TME) of advanced melanoma. These cells work with the tumor cells to suppress host development of anti-tumor immune responses, regulate tumor metastasis, and drive cancer drug resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Goals: Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we investigated the immune activation induced by BG34-200-CD11b engagement in the context of advanced melanoma and use the knowledge to develop BG34-200-based combination immunotherapy. Methods: Wild type B57Bl6/J mice were injected with 1.5million B16F10 cells and treated intravenously with BG34-200. Tumor volume and animals survival were monitored, and whole blood was drawn for FACS analysis. Results: We found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes where they triggered the generation of tumor antigen specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T-cell to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor cell challenge. Conclusions: The scientific findings from this study will allow us to develop new technology to apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy. Citation Format: Veronique P. Roche, Victor Sandoval, Zachary Senders, Joshua Lyons, Claire Wolford, Mei Zhang. BG34-200 immunotherapy of advanced melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2280.

The HORIZON III retrospective exploratory analysis: HER2 expression amplification in colorectal cancer.

194 Background: Although regularly used in breast and gastric cancer, HER2 testing is not routinely performed in colorectal cancer (CRC). Immunohistochemistry (IHC) and in situ hybridization (ISH) scoring have not been optimized for assessment of HER2 overexpression and amplification in CRC. Varying rates of HER2 overexpression (2%-11%) have been reported in previously untreated CRC (Wang World J Gastrointest Oncol 2019) and patients with advanced/metastatic CRC with HER2 amplification or overexpression respond poorly to current standard of care therapies (Sartore-Bianchi Oncologist 2019). We characterized HER2 prevalence in a retrospective cohort analysis of clinical trial patients. Methods: The HORIZON III trial (NCT00384176) evaluated FOLFOX + bevacizumab or cediranib (AZD2171) as first-line (1L) treatment in patients with metastatic CRC (Schmoll J Clin Oncol 2012). The primary objective of this analysis of a subset of HORIZON III samples was to characterize HER2 prevalence in 1L metastatic CRC. Secondary and exploratory objectives included correlating HER2 status to other molecular findings (eg, RAS/RAF mutations), clinicopathologic characteristics, and patient outcomes. IHC was performed using a monoclonal anti-HER2 antibody PATHWAY HER2 [4B5] Ventana on primary CRC tumor sections and scored according to ASCO/CAP guidelines for gastric cancer (Bartley Arch Pathol Lab Med 2016). H&E staining was performed to determine the adequacy of tumor samples (ie, > 100 viable tumor cells per specimen). All tumors with an IHC score of 2+ were analyzed for amplification by ISH (HER2 IQFISH pharmDx dual probe kit, Agilent Technologies K573111-5). Targeted mutation panel testing was used to determine other molecular alterations. Descriptive statistics were used to summarize baseline and clinical outcome data by HER2 status. The current analysis was approved by the AstraZeneca bioethics review board. Results: Of the 1614 patients in HORIZON III, 396 met the inclusion criteria of appropriate consent, sufficient tumor sample for analysis, and a unique identifier. HER2-positive tumors (IHC3+ or IHC2+/ISH+) were identified in 2.1% of samples; 1.3% were IHC3+ and 0.8% were IHC2+/ISH+. Compared with IHC3+, IHC2+ tumors were more heterogeneous with mixed components of cells weakly expressing HER2 and lacking HER2 expression. Conclusions: This exploratory analysis of the HORIZON III study provides insights into HER2 prevalence in 1L, unselected, advanced/metastatic CRC, finding that 2.1% of tumors were HER2 positive. The demographic characteristics of patients with analyzable samples were representative of the entire HORIZON III study population; however, further assessment of KRAS status and other clinicopathological characteristics is needed. These data may inform future clinical development and support selection of patients with CRC who are likely to benefit from HER2 targeting therapies. Clinical trial information: NCT00384176 .

Reducing Dietary Acid With Fruit and Vegetables Versus Oral Alkali in People With Chronic Kidney Disease (ReDACKD): A Clinical Research Protocol.

Individuals with chronic kidney disease (CKD) can develop metabolic acidosis which, in turn, is associated with faster progression of CKD and an increased need for dialysis. Oral sodium bicarbonate (the current standard of care therapy for metabolic acidosis) is poorly tolerated leading to low adherence. Base-producing or alkalizing Fruit and vegetables have potential as an alternative treatment for metabolic acidosis as they have been shown to reduce acid load arising from the diet. This trial will evaluate the feasibility of providing base-producing fruit and vegetables as a dietary treatment for metabolic acidosis, compared with oral sodium bicarbonate. A 2-arm, open-label, dual-center, randomized controlled feasibility trial. Two Canadian sites: a nephrology clinic in Winnipeg, Manitoba, and a nephrology clinic in Halifax, Nova Scotia. Adult participants with G3-G5 CKD and metabolic acidosis. Participants will undergo baseline measurements and attend 5 study visits over 12 months at which they will have a measurement of feasibility criteria as well as blood pressure, blood and urine biochemistry, 5-repetition chair stand test (STS5), and questionnaires to assess quality of life and symptoms. Furthermore, participants fill out Automated Self-Administered 24-hour recalls (ASA-24) in the beginning, middle, and end of trial. A total of 40 eligible participants will be randomized 1:1 to either base-producing fruit and vegetables (experimental) group or sodium bicarbonate (control) group, beginning from a daily dose of 1500 mg. Using self-administered dietary assessments, lack of supervision over the consumption of study treatments and the possible disappointment of the control group for not receiving fruit and vegetables would be considered as limitations for this study. However, we are planning to undertake proper practices to overcome the possible limitations. These practices are discussed throughout the article in detail. This study will generate data on base-producing fruit and vegetables consumption as a dietary treatment for metabolic acidosis in CKD. The data will be used to design a future multi-center trial looking at slowing CKD progression in people with metabolic acidosis. This study is registered on clinicaltrials.gov with the identifier NCT05113641.

BG34-200 Immunotherapy of Advanced Melanoma.

High levels of myeloid-derived cells are characteristic of the tumor microenvironment (TME) of advanced melanoma. These cells interact with tumor cells to suppress the development of antitumor immune responses, regulate tumor metastasis, and drive cancer's resistance to virtually all types of therapy. Therefore, methods to disrupt tumor-associated myeloid cell function are actively being sought to find a cure. Our team has recently developed a plant-derived carbohydrate molecule, BG34-200, that modulates tumor-associated myeloid cells by targeting the cell surface receptor CD11b. In this study, we found that BG34-200 IV administration could significantly inhibit tumor growth and improve survival in B16F10 mice with advanced melanoma. Our data supported a model that the entry of BG34-200 into circulating melanoma tumor-associated inflammatory monocytes (TAIMs) could trigger a sequential immune activation: the BG34-200+ TAIM subsets migrated to tumor and differentiated into monocyte-derived dendritic cells (mo-DCs); then, the BG34-200+ mo-DCs migrated to tumor draining lymph nodes, where they triggered the generation of tumor-antigen-specific T cells. Based upon these results, we combined BG34-200 treatment with adoptive transfer of TdLN-derived T cells to treat advanced melanoma, which significantly improved animal survival and helped tumor-free survivors be resistant to a second tumor-cell challenge. The scientific findings from this study will allow us to develop new technology and apply BG34-200-based immunotherapy to patients with advanced melanoma who have not responded to current standard of care therapies with and without immunotherapy.

Acid Ceramidase (ASAH1) Is a Key Mediator of Drug Resistance in Refractory Multiple Myeloma

Despite the growing armamentarium of treatments including proteasome inhibitors (PIs), immunomodulatory imides (IMiDs) and cellular and non-cellular immunotherapies MM remains incurable, due to the emergence of drug resistance that causes patient relapse. To develop therapies that significantly extend overall survival, a clearer understanding of the mechanisms driving drug-resistance is urgently required. Analysis of RNA-seq data derived from 672 MM Moffitt patients revealed that sphingolipid metabolism genes and in particular acid ceramidase (ASAH1), are significantly enriched in relapse MM (RMM). Further, high levels of ASAH1 in RMM patients predicted poorer overall survival when patients were treated with any PI-containing regimen (median overall survival 552 vs 1226 days). These findings were corroborated in the Multiple Myeloma Research Foundation CoMMpass dataset (IA17). Next, we queried potential mechanisms of treatment resistance using gene-set enrichment analysis (GSEA). ASAH1 High patients displayed upregulation of gene signatures involved in metabolism of lipids, sphingolipids and regulation of apoptosis. Further, PI-resistant cell lines (U266-PSR, RPMI8226-B25, and ANBL6-V10R) displayed elevated levels of ASAH1, and total and phosphorylated levels of anti-apoptotic proteins MCL-1 and BCL-2 compared to PI-sensitive parental cells (U266, RPMI8226 and ANBL6). Genetic (shRNA) and pharmacological (ceranib-2) inhibition of ASAH1 significantly decreased MM viability and reduced MCL-1/BCL-2 expression. Further, ASAH1 inhibition resensitized resistant MM cells to PI treatment. Importantly, we recapitulated our findings in CD138+ patient MM cells ex vivo (EMMA platform), with ceranib-2/PI treatment being synergistic in the majority (>75%) of patient samples tested. In vivo, ceranib-2 treatment limited PI-resistant U266-PSR MM tumor growth and extended overall survival of NSG mice. Further, ASAH1 depletion (shRNA) resensitized MM cells to PI treatment in vivo and loss of MCL-1 and BCL-2 expression was confirmed ex vivo. To understand the mechanism through which ASAH1 mediates PI-resistance we performed total and pSTY proteomic profiling (LC-MS/MS). Proteomic analyses revealed inhibition of the endogenous phosphatase PP2A inhibitor, I2PP2A as a candidate mechanism. Notably, I2PP2A was elevated in PMRC RMM patient samples, correlating with ASAH1 expression, and predicting poorer overall survival. In conclusion, in vitro, in vivo and patient ex vivo data demonstrate ASAH1 is a novel, clinically relevant and tractable target for the treatment of PI-resistant MM. Future studies to develop novel and potent ASAH1 inhibitors for the treatment resistant MM, in combination with current standard of care therapies are on-going and we believed warranted based on our emerging data.

Abstract IA018: ATP production in pancreas cancer and tumor infiltrating lymphocytes

Abstract Diet can influence both the microbiome and (at least in mice) the outcomes of pancreas cancer therapy. For example, ketogenic diet can synergize with either current standard of care therapy ( gemcitabine + nab-paclitaxel) or PI3K inhibition in mouse models of pancreas cancer. I will discuss our recent work exploring how diet interacts with the microbiome, and how such interactions may influence pancreas cancer chemotherapy response. A simple hypothesis for how diet influences microbiome composition is that certain microbes prefer certain nutrients, and diets high in those nutrients lead to outgrowth of those microbes. To enable testing of this hypothesis, we developed isotope-tracer strategies that directly measure the nutrient preferences of different members of the gut microbiome. I will describe this new technology and its application to support the above hypothesis. I will further describe experiments manipulating diet and/or microbiome to influence the response of pancreas cancer to PI3K inhibition. The longterm goal is to understand, at a biochemical level, the links between diet, microbiome, and the effectiveness of cancer therapy, and to develop translatable strategies for manipulating metabolism via diet to improve therapeutic outcomes. Citation Format: Joshua D. Rabinowitz. ATP production in pancreas cancer and tumor infiltrating lymphocytes [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr IA018.

204. THE TUMOUR IMMUNE MICROENVIRONMENT IN OESOPHAGEAL ADENOCARCINOMA HAS PROGNOSTIC SIGNIFICANCE

Abstract Oesophageal adenocarcinoma (OAC) is a deadly disease with an increasing incidence globally. Treatment outcomes with traditional therapy have largely plateaued and responses to immunotherapy are modest at best, necessitating the need for better biomarker driven selection. We aimed to unravel the tumour neoantigen landscape and immune microenvironment in OAC patients to aid improved patient selection and inform novel immunotherapy trials. To characterise the tumour immune microenvironment and neoantigen landscape of OACs, we performed DNA sequencing (n = 117) and RNA sequencing (n = 115) on biopsies taken at pre-treatment endoscopy. Using expression-based computational methods we analysed transcriptomic data to profile infiltration levels of 28 immune cell populations and their functional orientation, as well as stromal signatures and immune checkpoint molecules. TCGA data was used for as a validation cohort. Tumour neoantigens were predicted using the pVAC-Seq pipeline. Using an immune based classification based on the tumour microenvironment composition, we identified three distinct phenotypes; immune-enriched (IE), heterogeneously-infiltrated (HI), and immune-cold (IC). The IE group showed improved survival compared to both HI and IC, with HI showing the worst survival. The HI-group showed no difference in stromal scores to the IE group, but showed significantly decreased adaptive-immune cell infiltration, indicating that an immunosuppressive stromal compartment may be driving outcomes for these patients. No difference was seen in total or quality neoantigen load between groups, but high correlation with antigen processing machinery is seen. Our analysis expands the knowledge of the relatively unknown tumour immune microenvironment of OAC. We have identified three immune TME-phenotypes with prognostic utility with current standard of care therapies; which may also act as potential immunotherapy biomarkers. This is being explored further in ongoing immune microenvironment research and will guide future translational studies.

Combinatorial treatments of tamoxifen and SM6Met, an extract from Cyclopia subternata Vogel, are superior to either treatment alone in MCF-7 cells.

Synergistic drug combinations are not only popular in antibiotic, anti-microbial, immune disease (i.e., AIDS) and viral infection studies, but has also gained traction in the field of cancer research as a multi-targeted approach. It has the potential to lower the doses needed of standard of care (SOC) therapeutic agents, whilst maintaining an effective therapeutic level. Lower dosages could ameliorate the fundamental problems such as drug resistance and metastasis associated with current SOC therapies. In the current study, we show that the combination of SM6Met with (2)-4-hydroxytamoxifen (4-OH-Tam, the active metabolite of tamoxifen) produces a strong synergistic effect in terms of inhibiting MCF7 ER-positive (ER+) breast cancer cell proliferation and that a 20 times lower dose of 4-OH-Tam in combination with SM6Met is required to produce the same inhibitory effect on cell proliferation as 4-OH-Tam on its own. Cell cycle analyses of the best combination ratios of SM6Met and 4-OH-Tam also suggests that the combination results in increased accumulation of cells in the S-phase and in the apoptotic phase. Moreover, the best combination ratio (20:1) of SM6Met with 4-OH-Tam displayed greater anti-metastatic potential in terms of inhibiting ER+ breast cancer cell migration, invasion, and colony formation than the SOC therapy alone, suggesting that SM6Met together with 4-OH-Tam could be a viable drug combination for not only delaying resistance and ameliorating the negative side-effects associated with current SOC therapies, like tamoxifen, but could also provide a novel, more affordable therapeutic alternative for treating or preventing ER+ breast cancer metastasis.

Challenges in Glioblastoma Radiomics and the Path to Clinical Implementation

Simple SummaryGlioblastoma (GBM) is a cancer with poor prognosis, its 5-year survival expectation is approximately 5%. Advances in oncologic treatment techniques have not led to significant improvements in survival outcomes for GBM patients. Part of the reason for the treatment failures in GBM patients is that treatments fail to account for heterogeneities both within and between different tumors. Radiomics is a rapidly emerging research field that examines the relationship between medical imaging features and patient clinical outcomes and biological characteristics of tumours. This review outlines the applications of radiomics for GBM patient management and the barriers facing the implementation of radiomics into clinical practice. In completing this review, we hope to inform clinicians and researchers on how radiomics may be used to improve patient clinical outcomes.Radiomics is a field of medical imaging analysis that focuses on the extraction of many quantitative imaging features related to shape, intensity and texture. These features are incorporated into models designed to predict important clinical or biological endpoints for patients. Attention for radiomics research has recently grown dramatically due to the increased use of imaging and the availability of large, publicly available imaging datasets. Glioblastoma multiforme (GBM) patients stand to benefit from this emerging research field as radiomics has the potential to assess the biological heterogeneity of the tumour, which contributes significantly to the inefficacy of current standard of care therapy. Radiomics models still require further development before they are implemented clinically in GBM patient management. Challenges relating to the standardisation of the radiomics process and the validation of radiomic models impede the progress of research towards clinical implementation. In this manuscript, we review the current state of radiomics in GBM, and we highlight the barriers to clinical implementation and discuss future validation studies needed to advance radiomics models towards clinical application.