Cancer Solid Tumors Research Articles

Trends in complexity of single-agent and combination therapies for solid tumor cancers approved by the US Food and Drug Administration.

Many FDA-approved cancer therapies, whether as a multiagent combination or as a single agent, have demonstrated only modest clinical benefit. To investigate the drug development landscape, this analysis focuses on whether newly approved drugs are added to existing standards as combination therapy or replace a former drug as monotherapy. A retrospective analysis of package inserts and corresponding trials for the treatment of nonhematology solid tumor malignancies from January 2011 to December 2023 was conducted to categorize an approval as monotherapy or combination therapy. Drug characteristics, treatment indications, study design, approval history, and efficacy results were compared between the 2 cohorts. Among the 292 approval entries and 110 drugs, 193 (66.1%) were monotherapies and 99 (33.9%) were combinations. Combinations, when compared with monotherapies, were more frequently approved as regular than accelerated approval (85 [85.9%] vs 132 [68.4%], P <.01), in the first-line setting (66 [66.7%] vs 69 [35.8%], P <.01), and with overall survival as the criteria (49 [49.5%] vs 40 [20.7%], P <.01). Monotherapies were more likely to be novel drugs compared with combinations (80 [41.5%] vs 14 [14.1%] P <.01). Monotherapies were more likely to be small molecule targeted agents, while combinations were more likely to be immunotherapies (P <.02). There was no difference comparing the time-to-event endpoints and validated clinical benefit scale, but the median response rate of combinations (46%) was higher than monotherapies (34%, P <.01). Given that clinical benefit appears limited in combination therapy compared with monotherapy, drug development could focus on simplifying cancer therapies toward patient-centered paradigms.

Delivery of differentiation therapy into solid tumor cancer stem-like cells to prevent metastasis and recurrence

Abstract. The concept of differentiation therapy offers an attracting explanation for plenty of clinical observations, such as relapse and metastasis. Its hallmark success has been in the treatment of acute promyelocytic leukaemia, a condition that is now highly curable through the combination of retinoic acid (RA) and arsenic. Recently, the finding of cancer stem-like cells (CSCs) triggers more attentions due to its unique high tumourigenicity and chemoresistance., which reside in hypoxic tumor regions, and are characterized by high tumourigenicity and chemoresistance. Considerable efforts have been made to develop promising anti-CSC strategies, including blocking surface biomarkers and inhibiting self-renewal signaling pathways. In this study, we engineered a liposomal delivery strategy that enables the codelivery of RA and arsenate, aiming to differentiate and potentiate CSCs. The core of the liposome is formed through coordination polymerization between arsenate and Calcium, while the membraneincorporates RA and helper lipids. We evaluated their cytotoxicity against cultured CSCs and their potential to differentiate CSCs into less malignant phenotypes.

Abstract PR006: The potential of multi-cancer early detection screening for reducing cancer mortality

Abstract Background: Currently, routine screening is recommended for only four cancer types (i.e., breast, cervical, colorectal, and lung) by the United States Preventive Services Task Force (USPSTF), and two-thirds of incident cancers have no screening guidelines. Emerging liquid biopsy multi-cancer early detection (MCED) tests have the potential to revolutionize early cancer detection. Their impact on cancer mortality remains uncertain. Computer models are needed to forecast long-term outcomes. Methods: We developed Simulation Model for MCED (SiMCED), a continuous-time, discrete-event microsimulation model of 14 solid tumor cancers: breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, kidney, liver, lung, ovarian, pancreatic, prostate, and urinary bladder. Cancer type- and stage-specific dwell times informed the transitions between cancer stages I-IV. Cancer type- and stage-specific MCED test sensitivities were derived from a large, multi-center, prospective, case-control study: Ascertaining Serial Cancer patients to Enable New Diagnostic 2 (ASCEND-2). The model was calibrated to reproduce annual incidence rates of cancer diagnosis as captured in the Surveillance, Epidemiology, and End Results (SEER) database, while accounting for the unobserved cancer burden. Using a 10-year time horizon, we simulated the life course of 5 million US adults aged 50-84 years, representative of the US population age distribution. Cancer diagnosis could arise from usual care or annual MCED screening. The MCED test was administered at the beginning of each year to individuals aged 50-84 years. After a cancer diagnosis, individuals followed SEER survival curves to determine the time and cause of death (cancer- or non-cancer-related). Results: Over the 10-year time horizon, the supplemental use of MCED screening reduced stage IV incidence by 876 (42%) per 100,000, relative to usual care. The 10-year reduction in cancer mortality was 439 (17%) per 100,000, which translates to 505,600 cancer-related deaths averted among US adults aged 50-84 years. Lung cancer had the highest absolute 10-year cancer mortality reduction at 126 (13%) per 100,000. Among the cancer types for which there is no routine screening, the 10-year cancer mortality reduction was 175 (15%) per 100,000, equating to 201,500 cancer-related deaths averted among US adults aged 50-84 years. Within the 10-year time window, earlier diagnosis by MCED led to an aggregated life-year gain of 1,165 per 100,000, which translates to a gain of 1,340,000 life-years among US adults aged 50-84 years. Conclusion: Our study suggests that MCED screening could be effective for reducing both stage IV incidence and cancer mortality. The real-world impact of MCED tests and their cost-effectiveness require further investigation. Citation Format: Jagpreet Chhatwal, Jade Xiao, Andrew ElHabr, Christopher Tyson, Xiting Cao, Sana Raoof, A. Mark Fendrick, A. Burak Ozbay, Paul Limburg, Tomasz M. Beer, Ashish Deshmukh, Andrew Briggs. The potential of multi-cancer early detection screening for reducing cancer mortality [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr PR006.

BIOM-53. LOW-PASS WHOLE GENOME SEQUENCING OF CEREBROSPINAL FLUID IDENTIFIES TUMOR AGNOSTIC TP53 ABERRATIONS IN LEPTOMENINGEAL METASTATIC DISEASE

Abstract Leptomeningeal metastatic disease (LMD) is the spread of cancer cells into the cerebrospinal fluid (CSF)-filled spaces surrounding the central nervous system (CNS). Once LMD occurs, patients endure devastating neurologic symptoms and survive for only a few weeks to months. The clinical diagnosis of LMD has risen as patient survival from non-CNS metastatic disease improves. Unfortunately, detection of LMD even in symptomatic patients is &amp;lt;50% using the current gold standard – CSF cytology. Therefore, a strong clinical need exists for the sensitive and early detection of LMD. Here, we sought to develop a minimally invasive liquid biopsy approach to diagnose LMD using next-generation sequencing. Because copy number variations (CNVs) are common in cancer and increase after chemoradiation, we hypothesized that CNV detection in CSF may offer a means to detect LMD since patients have already undergone treatment for the underlying disease. Specifically, we sought to develop low-pass whole genome sequencing (lpWGS) of cell-free DNA in CSF to detect CNVs associated with LMD. A novel lpWGS algorithm was developed using FASTQ files trimmed to 30 million total paired reads. The genome was partitioned into one million continuous base pair segments excluding problematic areas yielding 2,445 regions across 22 autosomes. Control samples were used to model the read depth for each region to establish the euploid state. Read depth across the genome for all samples was 0.6X. CSF samples from lung cancer, breast cancer, and melanoma patients with LMD demonstrated prominent evidence of monosomies and trisomies throughout the genome. Lung cancer exhibited frequent amplifications (&amp;gt;4-fold). Notably, we observed 17p monosomy in CSF regardless of cancer type which indicates TP53 haploinsufficiency may support LMD progression, a conjecture supported by a codeletion of TP53 in one patient. lpWGS detects LMD in solid tumor cancers and may also identify novel mechanisms for LMD progression.

Clinical characteristics associated with hospital-onset bacteremia and fungemia among cancer and transplant patients.

This study quantified the burden of hospital-onset bacteremia and fungemia (HOB) among cancer and transplant patients compared to other patients. A retrospective cross-sectional study used data from 41 hospitals between October 2015 and June 2019. Hospitalizations were segmented into categories using diagnosis-related groups (DRG): myeloproliferative (MP) cancer, solid tumor cancer, transplant, and non-cancer/non-transplant ("reference group"). To quantify the association between DRG and HOB, multivariable adjusted Poisson regression models were fit. Analyses were stratified by length of stay (LOS). Of 645,315 patients, 59% were female and the majority 41 years of age or older (76%). Hospitalizations with MP cancer and transplant demonstrated higher HOB burden compared to the reference group, regardless of LOS category. For all hospitalizations, the >30 days LOS category had a higher burden of HOB. The median time to reportable HOB was within 30 days regardless of duration of hospitalization (reference, 8 days; solid tumor cancer, 8 days; transplant, 12 days; MP cancer, 13 days). MP cancer and transplant patients had a higher burden of HOB compared to other hospitalized patients regardless of LOS. Whether these infections are preventable should be further evaluated to inform quality metrics involving reportable bacteremia and fungemia.

Application of novel CAR technologies to improve treatment of autoimmune disease.

Chimeric antigen receptor (CAR) T cell therapy has become an important treatment for hematological cancers, and its success has spurred research into CAR T cell therapies for other diseases, including solid tumor cancers and autoimmune diseases. Notably, the development of CAR-based treatments for autoimmune diseases has shown great progress recently. Clinical trials for anti-CD19 and anti-BCMA CAR T cells in treating severe B cell-mediated autoimmune diseases, like systemic lupus erythematosus (SLE), have shown lasting remission thus far. CAR T cells targeting autoreactive T cells are beginning clinical trials for treating T cell mediated autoimmune diseases. Chimeric autoantigen receptor (CAAR) T cells specifically target and eliminate only autoreactive B cells, and they have shown promise in treating mucosal pemphigus vulgaris and MuSK myasthenia gravis. Regulatory CAR T cells have also been developed, which show potential in altering autoimmune affected areas by creating a protective barrier as well as helping decrease inflammation. These new treatments are only the beginning of potential CAR T cell applications in treating autoimmune disease. Novel CAR technologies have been developed that increase the safety, potency, specificity, and efficacy of CAR T cell therapy. Applying these novel modifications to autoimmune CARs has the potential to enhance the efficacy and applicability of CAR therapies to autoimmune disease. This review will detail several recently developed CAR technologies and discuss how their application to autoimmune disease will improve this emerging field. These include logic-gated CARs, soluble protein-secreting CARs, and modular CARs that enable CAR T cell therapies to be more specific, reach a wider span of target cells, be safer for patients, and give a more potent cytotoxic response. Applying these novel CAR technologies to the treatment of autoimmune diseases has the potential to revolutionize this growing application of CAR T cell therapies.

Assessing outcomes for patients receiving chemotherapy in the intensive care unit.

190 Background: Despite the low in-hospital mortality rate (9%) for Intensive Care Unit (ICU) stays in the US, outcomes for patients with cancer undergoing chemotherapy in the ICU remains unclear. We aimed to assess survival in patients with cancer (liquid, solid tumor and allogeneic stem cell transplant (alloSCT) receiving chemotherapy at our institution and identify patient characteristics for enhanced chemotherapy stewardship. Methods: We analyzed pharmacy data for patients with confirmed malignancies who received chemotherapy while admitted to the ICU at our institution from 1/1/21 to 12/31/23, excluding non-cancer patients and those on home oral regimens. Primary endpoints included 14-day, 30-day, and 90-day survival. Secondary analyses examined survival differences by age, ECOG performance status, and treatment history. Survival differences among patient subtypes were evaluated using Z-tests. Results: We identified 74 unique patients who received chemotherapy for cancer. 54 had liquid tumors, 5 were post-alloSCT, and 15 had solid tumors. The 90-day survival rate was 47% overall: 46% for the liquid tumor group, 80% for the alloSCT group, and 40% for the solid tumor group. When further stratified by tumor type, higher 90-day survival was variable; see Table 1 for details). In patients with lung cancer, 90-day survival was worse for non-small cell lung cancer without tumor mutations (0%, n=2) than those with targetable mutations (50%, n=4) or small cell lung cancer (33%, n=3). An ECOG performance status of 3-4 showed poorer 90-day survival in liquid tumors (23%) compared to ECOG 1-2 (74%; 95% CI 0.26 , 0.76). Solid tumors showed no significant ECOG differences (50%, 40%). Treatment-naive status showed higher 90-day survival in liquid tumors (59%) compared to treatment-resistant tumors (18%; 95% CI 0.17, 0.65), but not in solid tumors (50%, 20%). Conclusions: Our findings suggest generally unfavorable 90-day outcomes for ICU chemotherapy patients, especially those aged over 75, with multiple therapy lines, or ECOG status 3-4. Survival rates varied significantly across tumor types. We are currently broadening our study to include all solid tumor cancer patients. While this is a limited sample, this underscores the need for careful chemotherapy stewardship and advanced care planning in ICU settings. 90-day survival of solid and liquid tumor patients receiving chemotherapy in the ICU by select cancer diagnoses. Cancer Diagnosis n 90-Day Survival (%) AML 20 45 DLBCL 16 33 APML 6 83 Multiple myeloma 5 60 Other liquid tumors 1 11 45 Lung cancer 9 44 Germ cell tumor 2 100 Hormone-sensitive breast cancer 1 100 Other solid tumors 2 3 0 1 T-cell lymphoma, ALL, CNS lymphoma, Castleman, MPN, and plasmablastic lymphoma. Note, patients with allogenic stem cell transplants not included. 2 Carcinoma of unknown primary, colon adenocarcinoma, multiple solid tumors.

Validation of Non-Small Cell Lung Cancer Clinical Insights Using a Generalized Oncology Natural Language Processing Model.

Limited studies have used natural language processing (NLP) in the context of non-small cell lung cancer (NSCLC). This study aimed to validate the application of an NLP model to an NSCLC cohort by extracting NSCLC concepts from free-text medical notes and converting them to structured, interpretable data. Patients with a lung neoplasm, NSCLC histology, and treatment information in their notes were selected from a repository of over 27 million patients. From these, 200 were randomly selected for this study with the longest and the most recent note included for each patient. An NLP model developed and validated on a large solid and blood cancer oncology cohort was applied to this NSCLC cohort. Two certified tumor registrars and a curator abstracted concepts from the notes: neoplasm, histology, stage, TNM values, and metastasis sites. This manually abstracted gold standard was compared with the NLP model output. Precision and recall scores were calculated. The NLP model extracted the NSCLC concepts with excellent precision and recall with the following scores, respectively: Lung neoplasm 100% and 100%, NSCLC histology 99% and 88%, histology correctly linked to neoplasm 98% and 79%, stage value 98.8% and 92%, stage TNM value 93% and 98%, and metastasis site 97% and 89%. High precision is related to a low number of false positives, and therefore, extracted concepts are likely accurate. High recall indicates that the model captured most of the desired concepts. This study validates that Optum's oncology NLP model has high precision and recall with clinical real-world data and is a reliable model to support research studies and clinical trials. This validation study shows that our nonspecific solid tumor and blood cancer oncology model is generalizable to successfully extract clinical information from specific cancer cohorts.

A novel tumor-derived exosomal gene signature predicts prognosis in patients with pancreatic cancer.

Pancreatic cancer is a devastating disease with poor prognosis. Accumulating evidence has shown that exosomes and their cargo have the potential to mediate the progression of pancreatic cancer and are promising non-invasive biomarkers for the early detection and prognosis of this malignancy. This study aimed to construct a gene signature from tumor-derived exosomes with high prognostic capacity for pancreatic cancer using bioinformatics analysis. Gene expression data of solid pancreatic cancer tumors and blood-derived exosome tissues were downloaded from The Cancer Genome Atlas (TCGA) and ExoRBase 2.0. Overlapping differentially expressed genes (DEGs) in the two datasets were analyzed, followed by functional enrichment analysis, protein-protein interaction networks, and weighted gene co-expression network analysis (WGCNA). Using the least absolute shrinkage and selection operator (LASSO) regression of prognosis-related exosomal DEGs, a tumor-derived exosomal gene signature was constructed based on the TCGA dataset, which was validated by an external validation dataset, GSE62452. The prognostic power of this gene signature and its relationship with various pathways and immune cell infiltration were analyzed. A total of 166 overlapping DEGs were identified from the two datasets, which were markedly enriched in functions and pathways associated with the cell cycle. Two key modules and corresponding 70 exosomal DEGs were identified using WGCNA. Using LASSO Cox regression of prognosis-related exosomal DEGs, a tumor-derived exosomal gene signature was built using six exosomal DEGs (ARNTL2, FHL2, KRT19, MMP1, CDCA5, and KIF11), which showed high predictive performance for prognosis in both the training and validation datasets. In addition, this prognostic signature is associated with the differential activation of several pathways, such as the cell cycle, and the infiltration of some immune cells, such as Tregs and CD8+ T cells. This study established a six-exosome gene signature that can accurately predict the prognosis of pancreatic cancer.

Steroidal 21-imidazolium salt derivatives: Synthesis and anticancer activity

Nitrogen-containing steroids are known as prostate cancer therapeutics. In this work, a series of pregnane derivatives bearing an imidazolium moiety were synthesized using Δ16-20-ketones as starting material. An improved approach for the construction of the 20-keto-21-heterocycle-substituted fragment involved the rearrangement of 16,17-epoxides with HCl, followed by reaction of the formed α-chloroketone with 1-substituted imidazoles. Binding affinity analysis of the imidazolium steroids and their synthetic intermediates to human CYP17A1 showed only type I (substrate-like) interactions. The strongest affinity was observed for 16α,17α-epoxy-5α-pregnan-20-on-3β-ol (Kd = 0.66 ± 0.05 µM). The steroid derivatives have been evaluated for antitumor activity against a range of prostate cancer cells as well as against various other solid tumor and hematologic cancer cell lines. All 21-imidazolium salts were active against the hormone-dependent prostate cancer line LNCaP. The most pronounced cytotoxicity in solid tumor and hematologic cancer cell lines was observed for intermediate product, 21-chloro-5α-pregn-16-en-20-on-3β-ol. Among the imidazolium salts, the derivatives with a single bond were more cytotoxic than their unsaturated congeners.

Misuse of Prescribed and Nonprescribed Substances Among U.S. Cancer Survivors.

Substance misuse is common among cancer survivors and can negatively impact cancer outcomes. We conducted a cross-sectional study using National Survey on Drug Use and Health data for 2015 to 2020. We included adult respondents with a history of solid tumor cancer. We calculated the weighted prevalence and corresponding SEs (both expressed as percentages) of substance (alcohol, opioid, sedative, stimulant, other) misuse for respondents with any history of solid tumor cancer and, in secondary analyses, respondents diagnosed with cancer in the prior 12months. The study included 6,101 respondents with any history of cancer, 1,437 diagnosed in the prior 12months. Alcohol was the most commonly misused substance. The average prevalence of alcohol misuse was 14.4% (SE 0.60%) across cancer types; it was markedly more common among people with a history or cervical (24.2% [3.0%]) or head and neck cancer (27.4% [7.1%]). The next most common form of substance misuse was opioid misuse (average prevalence: 2.7% [0.25%]). As with alcohol misuse, the prevalence of opioid misuse was higher among those with a lifetime history of cervical cancer (5% [1%]) or head and neck cancer (5% [3%]). Results were generally consistent among cancer survivors diagnosed in the prior 12months. There is a clear opportunity to address substance misuse-particularly alcohol misuse-among cancer survivors. Such efforts should focus on populations with a high prevalence of substance misuse (e.g., cervical and head and neck cancer survivors) and have strong potential to improve cancer-specific and overall health outcomes.

Comparative Study between Cyclosporine Dynamics and Other Immunosuppressants in Patients Post Allogenic Stem Cell Transplantation

Abstract Background Bone marrow transplant has been successfully to treat diseases such as leukemia, lymphomas, aplastic anemia, immune deficiency disorders, and some solid tumor cancers. There is two types of bone marrow transplantation, one of two types of transplant may be carried out either an autograft, using the patient’s own bone marrow cells or an allograft (or allogeneic transplant), which allows the replacement of the diseased bone marrow with an healthy bone marrow taken from a compatible donor (related or unrelated) and to use the immune system of the healthy donor to fight the recipient’s illness. Aim of the Work To assess impact of cyclosporine introduction post-transplant on different organs and other immune suppressant as regards side effects and prophylactic efficacy against GVHD and good outcome of the transplantation. Patients and Methods The study enrolled two groups, 128 post-transplant patient their ages between 16 and 65, group 1 include 106 patients was taking cyclosporine for prophylaxis of GVHD, group 2 include 22 patients was taking other immunosuppressants mainly Tacrolimus and MMF. Results Incidence of GVHD occurrence was lower in group of cyclosporine as 30.2 % of them has no GVHD with statistically significant difference with P-value 0.007 and was lower in combined occurrence of acute and chronic GVHD,22.6 % in group 1 and 54.5 % of group 2 with P-value 0.006 Incidence of mild anemia was lower in group 1 with statistically significant difference with P-value 0.022 Hyponatremia was higher in group 1 (60.4 %) with statistically significant difference with P-value 0.026 AST levels elevated one fold higher in group 1 with statistically significant difference with P-value 0.009 and elevated three fold higher in group 2 with statistically significant difference with P-value &amp;lt; 0.001 ALT levels elevated one fold higher in group 1 with statistically significant difference with P-value 0.039 21 patients were presented with impairment of renal functions,12.5% with mild impairment, 3.9 % with moderate impairment, all of them from group 1 with statistically significant difference with P-value 0.023, more commonly in females and in age group from 16 to 45 years old. Conclusion Hematopoietic stem cell transplantation (HSCT) is a particularly important treatment for hematologic malignant and nonmalignant diseases. Unfortunately, following allogeneic HSCT, graft-versus-host disease, immunosuppression and susceptibility to opportunistic infections remain among the most substantial problems restricting the efficacy and use of this procedure. Cyclosporine remains the most effective prophylaxis post HSCT for prevention of GVHD, more multi centric studies are needed on wide scale to prove more relevant results that will be significant.

Predominance of Candida glabrata in candidemia among patients with solid tumor cancer in Oman: A retrospective study

ObjectivesCandida species frequently cause bloodstream infections; however, there is a lack of epidemiological studies on candidemia in Oman. MethodsTo address this, we conducted a retrospective study at Sultan Qaboos Comprehensive Cancer and Research Center from October 2021 to October 2023. ResultsOur study identified 27 episodes of candidemia among 26 patients with cancer, with an incidence of 4.9 per 1000 admissions. Non-albicans Candida (NAC) prevailed over C. albicans (70.37% vs 29.62%), with C. glabrata as the predominant NAC species (n = 10; 37%). The 30-day mortality rate was 40.7%, showing no significant difference between NAC and C. albicans but was notably higher in critically ill patients (P = 0.03). ConclusionIn Oman, NAC surpasses C. albicans as a causative pathogen for candidemia with a high mortality rate.

Preoperative cognitive function as a risk factor of postoperative delirium in cancer surgeries: A systematic review and meta-analysis.

Postoperative delirium (POD) after cancer surgeries can be a result of chemo brain, anesthesia, surgery duration, and preoperative cognitive impairment. Although older age and preoperative cognitive dysfunction were reported to increase the risk of POD in noncardiac surgery, the role of preoperative cognitive function and age in the development of POD after all types of cancer surgeries is not clear. This study aimed to determine the relationship between preoperative cognitive function and likelihood of POD after cancer surgeries. This study used three main online databases and followed PRISMA guidelines. English language original articles that examined preoperative cognitive function before solid tumor cancer surgery and assessed patients for postoperative delirium were included. We employed the random effect meta-analysis method. The overall incidence of POD ranged from 8.7% to 50.9%. The confusion assessment method was the most common tool used to assess delirium. Mini-mental state evaluation (MMSE), Mini-cog, and Montreal cognitive assessment were the most common tools to assess cognitive function. The pooled (total observation = 4676) random effects SMD was estimated at -0.84 (95% confidence interval [CI]: -1.30 to -0.31), indicating that lower MMSE scores before surgery are associated with a higher risk of POD. The pooled (total observation = 2668) random effects OR was estimated at 5.17 (95% CI: 2.51 to -10.63), indicating preoperative cognitive dysfunction can significantly predict the occurrence of POD after cancer surgeries. In conclusion, preoperative cognitive function is an independent and significant predictor of POD after solid tumor cancer surgeries.

The mitochondrial calcium uniporter: Balancing tumourigenic and anti-tumourigenic responses.

Increased malignancy and poor treatability associated with solid tumour cancers have commonly been attributed to mitochondrial calcium (Ca2+) dysregulation. The mitochondrial Ca2+ uniporter complex (mtCU) is the predominant mode of Ca2+ uptake into the mitochondrial matrix. The main components of mtCU are the pore-forming mitochondrial Ca2+ uniporter (MCU) subunit, MCU dominant-negative beta (MCUb) subunit, essential MCU regulator (EMRE) and the gatekeeping mitochondrial Ca2+ uptake 1 and 2 (MICU1 and MICU2) proteins. In this review, we describe mtCU-mediated mitochondrial Ca2+ dysregulation in solid tumour cancer types, finding enhanced mtCU activity observed in colorectal cancer, breast cancer, oral squamous cell carcinoma, pancreatic cancer, hepatocellular carcinoma and embryonal rhabdomyosarcoma. By contrast, decreased mtCU activity is associated with melanoma, whereas the nature of mtCU dysregulation remains unclear in glioblastoma. Furthermore, we show that numerous polymorphisms associated with cancer may alter phosphorylation sites on the pore forming MCU and MCUb subunits, which cluster at interfaces with EMRE. We highlight downstream/upstream biomolecular modulators of MCU and MCUb that alter mtCU-mediated mitochondrial Ca2+ uptake and may be used as biomarkers or to aid in the development of novel cancer therapeutics. Additionally, we provide an overview of the current small molecule inhibitors of mtCU that interact with the Asp residue of the critical Asp-Ile-Met-Glu motif or through other allosteric regulatory mechanisms to block Ca2+ permeation. Finally, we describe the relationship between MCU- and MCUb-mediating microRNAs and mitochondrial Ca2+ uptake that should be considered in the discovery of new treatment approaches for cancer.

Sarcopenic Obesity and Outcomes for Patients With Cancer

The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) have recently proposed a consensus definition and diagnostic criteria for sarcopenic obesity (SO). To implement the ESPEN-EASO diagnostic algorithm to investigate the prevalence of SO and its association with outcomes in patients with solid tumor cancers, with particular regard to associations among SO, overall survival (OS), and patient quality of life (QoL). This prospective cohort study included patients diagnosed with solid tumor starting in May 7, 2013, with the last follow-up on June 30, 2022. Patients with solid tumors were categorized into SO and non-SO groups according to ESPEN-EASO criteria. The primary outcome was OS and the secondary outcomes included patient QoL and risk of intensive care unit (ICU) admission. Data were analyzed from June to December 2023. A total of 6790 patients were included in the study (mean [SD] age, 59.64 [10.77] years; 3489 were female [51.4%]). The prevalence of SO was 4.36% (296 of 6790) in the whole cohort and 14.98% (296 of 1976) in the subgroup with obesity. SO prevalence increased with age. During a median (IQR) follow-up period of 6.83 (5.67-7.04) years, 2103 patients died. Cox regression analysis indicated that SO was independently associated with lower OS (hazard ratio [HR], 1.54; 95% CI, 1.23-1.92), which was observed in both men (HR, 1.51; 95% CI, 1.09-2.10) and women (HR, 1.53; 95% CI, 1.12-2.07). SO was also associated with poorer QoL and higher risk of ICU admission (odds ratio, 2.39; 95% CI, 1.06-5.29). Among the diagnostic components of SO, low hand grip strength (HGS) was the only SO component associated with poor OS (HR, 1.15; 95% CI, 1.04-1.28). This cohort study of SO found that SO was significantly associated with lower OS, poorer QoL, and higher risk of ICU admission. Weak HGS, 1 of the diagnostic conditions, was the only component of SO associated with OS. The ESPEN-EASO algorithm appears to be an applicable tool to identify cancer-associated SO, which represents a major clinical complication and factor associated with risk for poor outcomes in these patients.

Association of immune checkpoint inhibitors with SARS-CoV-2 infection rate and prognosis in patients with solid tumors: a systematic review and meta-analysis.

https://www.crd.york.ac.uk/prospero/#recordDetails PROSPERO, identifier CRD42023393511.

Effect of placental circulating T cells expressing CD16 on multiple hematological and solid tumor cancers through combination with various monoclonal antibodies.

2554 Background: PT-CD16VS is an allogeneic cell therapy derived from human postpartum placental circulating T (PT) cells that are genetically modified to express CD16 and endogenous T cell receptor (TCR) knockout. PT-CD16VS cells can be combined with various monoclonal antibodies to engage in anti-tumor antibody-dependent cellular cytotoxicity (ADCC) against diverse cancers with a “universal receptor” approach. Here we report the characterization and preclinical evaluation of PT-CD16VS in combination with monoclonal antibodies against both hematological and solid tumor cancers. Methods: PT cells were activated, transduced with a lentiviral vector containing a construct expressing a high affinity CD16 variant, CD16VS, and transfected to knock out the TCR. In vitro,functional activity of PT-CD16VS cells in combination with monoclonal antibodies was assessed in cytotoxicity, cytokine release, and proliferation assays. Invivo, PT-CD16VS was combined with Rituximab in a Raji xenograft model in NSG mice, and with Trastuzumab in a subcutaneous NCI-N87 xenograft model in NSG mice in which tumor volume was measured and tumor samples were evaluated for PT-CD16VS infiltration. Results: In vitro, PT-CD16VS exhibited potent ADCC and cytokine release when combined with Rituximab against CD20+ Burkitt's lymphoma (Daudi and Raji), with Trastuzumab against HER2+ gastric carcinoma (NCI-N87), with Trastuzumab or Avelumab against HER2+/PDL-1+ non-small cell lung carcinoma (NCI-H1975) and Trastuzumab-resistant metastatic mammary adenocarcinoma (JIMT-1), and with Cetuximab against EGFR+ triple negative metastatic mammary adenocarcinoma (MDA-MB-231). Moreover, examples of PT-CD16VS antigen-specific proliferation were demonstrated against Raji and NCI-N87 when cells were combined with Rituximab and Trastuzumab, respectively. In vivo, in combination with Rituximab in the Raji mouse model, PT-CD16VS exhibited significant survival benefit compared to vehicle and Rituximab alone treated groups. In the subcutaneous NCI-N87 solid tumor model, PT-CD16VS with Trastuzumab demonstrated significant reduction in tumor volume compared to vehicle, Trastuzumab, and Enhertu groups. In addition, PT-CD16VS infiltration into the tumor was shown to be Trastuzumab dependent, with infiltrating cells expressing high levels of CD16 and Ki67. Conclusions: Our results show that PT-CD16VS have potent in vitro and in vivo ADCC activity, and a single drug product has the potential to be combined with various monoclonal antibodies to target multiple cancers across hematological and solid tumor indications. This “universal receptor” with antibody-dependent targeting approach, together with the benefits of an allogeneic cell platform, may democratize accessibility of such therapies for patients.

Phase 1 trial safety and efficacy of ragistomig, a bispecific antibody targeting PD-L1 and 4-1BB, in advanced solid tumors.

2529 Background: Activation of T cells in the tumor microenvironment by 4-1BB agonist antibodies is a promising approach to augment PD-(L)1 inhibitor efficacy. Ragistomig(ABL503/TJ-L14B) is a bispecific antibody combining PD-L1 antagonist with 4-1BB agonistic activity, designed to induce 4-1BB signaling only when bound to the PD-L1 tumor antigen on cancer cells, which may overcome resistance to PD-(L)1 inhibition and avoid hepatoxicity seen with traditional 4-1BB mAbs. Methods: ABL503 was investigated at doses ranging from 0.7 mg (flat dose) to 10 mg/kg (weight-based dose) IV every 2 weeks (Q2W) in patients with advanced or relapsed/refractory solid tumors, to assess safety, preliminary anti-tumor effect and pharmacokinetic (PK)/pharmacodynamic (Pd) activity. The BOIN design was utilized during dose escalation (regardless of CPS/TPS score). Additional patients were enrolled in dose expansion cohorts at 3 and 5 mg/kg (CPS/TPS&gt;=1 required). Results: As of Jan 2024, the study enrolled 49 patients (30 dose escalation, 19 dose expansion). At least 1 treatment related adverse event (TRAE) occurred in 37 patients (75.5%); most common TRAE (≥ 10%, any grade/grade 3-4) were elevated AST (30.6%/18.4%), elevated ALT (26.5%/18.4%), rash (14.3%/4.1%), nausea (12.2%/0%), pyrexia (12.2%/2.0%) and fatigue (10.2%/0%). Dose limiting toxicities occurred in 5 patients and were observed at dose levels of 1, 5, and 10 mg/kg. All DLTs were recovered/recovering. MTD was not reached. Based on the safety, efficacy, PK and Pd analysis, the optimal dose was determined to be 5 mg/kg Q2W. Objective responses were observed in 6 out of 39 efficacy-evaluable patients, and all responses were observed at 3 and 5 mg/kg, including 1 complete response (CR) in a patient with ovarian cancer who received 6 prior lines of treatment and 5 partial responses (PRs) in patients with ovarian (n=1), melanoma (n=1), gastric (n=1), head and neck squamous cell (n=1), and esophageal cancer (n=1). Overall response rate (ORR) for all dose levels was 15.3%, and ORR at 5 mg/kg was 30% (3/10). Clinical benefit rate (CBR) for all dose levels was 61.5%, and CBR at 5 mg/kg was 80% (8/10). 66.7% of responders received prior PD-(L)1 inhibitors. One patient achieved sustained tumor regression over 6 months, even after treatment discontinuation. PK was dose proportional, and half-life was ~5 days. Dose-dependent increase of Pd marker s4-1BB was observed, demonstrating target engagement. Conclusions: ABL503 had a manageable safety profile and demonstrated promising anti-tumor activity, with objective responses in 6 out of 39 efficacy-evaluable patients across multiple tumor types in heavily pre-treated patients, including patients previously treated with checkpoint inhibitors. The data support continued development of ABL503 alone and in combination with other compounds, as a potential therapeutic option for patients with solid tumor cancers. Clinical trial information: NCT04762641 .

Expression of alternatively spliced PD-L1 RNA with skipping of transmembrane domain.

e14596 Background: Programmed death-ligand 1 (PD-L1) is a transmembrane ligand for the programmed cell death protein 1 (PD-1), a receptor that inhibits T-cell activity. The PD-L1/PD-1 immune checkpoint axis has been successfully targeted to enhance antitumor immune responses. This gene is composed of seven exons. Exons 1-4 are responsible for the extracellular domain, exon 5 for the transmembrane domain, and exons 6-7 for the intracellular domain. Emerging data indicates that alternative splicing in genes is an important mechanism for expression of different isoforms that may influence antibody-based therapies. We explored the potential of the presence of alternative splicing in PD-L1 transcripts via sequencing of PD-L1 RNA in patients with various type of solid tumor cancers. Methods: RNA was extracted from 3443 FFPE solid tumor samples including lung, colon, pancreas, breast, and other cancer types. In addition, cfRNA was extracted from 532 peripheral blood plasma samples from patients with solid tumor cancers. RNA was sequenced using a hybrid capture targeted RNA panel on FFPE samples and peripheral blood with analysis focused on PD-L1 gene transcript. Quantification of RNA transcript was done using Salmon algorithm. Results: Of the 3443 FFPE samples, 38 (1.2%) samples showed alternative splicing involving deletion of exon 5 (PD-L1∆Ex5). The alternative splicing was in 2.10% of lung cancer, 2% of colon cancer, 0.70% of pancreatic cancer, 1.40% of gastric cancer, 0.38% of breast cancer, 0.30% of ovarian cancer, 1.10% of sarcoma cases, 1.50% of glioblastomas, 3.30% of thyroid cancer and 2% of urothelial cancer. Of the 532 cfRNA samples, 20 (3.7%) showed PD-L1∆Ex5. The median percentage of PD-L1∆Ex5 transcripts was 2.2% of total PD-L1 transcripts in tissue samples as compared with 6.6% in cfDNA samples. In tissue samples, there was a correlation between levels of PD-L1 and PD-L1∆Ex5 (r = .567, p &lt; .001). In contrast, cfRNA showed no significant correlation between levels of PD-L1 and levels of PD-L1∆Ex5 (r = .268). Conclusions: PD-L1 exon 5 skipping was detected in a number of patients with different types of solid tumor cancers. The percentage of skipping transcripts is low in cells and relatively higher in cfRNA. Since exon 5 skipping deletes the transmembrane domain, the PD-L1 protein may remain in the cytoplasm or perhaps is secreted as cell-free PD-L1 protein. The demonstration of relatively higher levels of PD-L1∆Ex5 in cfRNA is likely reflecting higher turnover of cells and raises the possibility that cells with this isoform of PD-L1 are more aggressive than cells without the expression of this isoform. Further studies are needed to explore the clinical relevance of the expression of such abnormal PD-L1 protein on treatment with immune checkpoint inhibitors.