Hematological Cancers Research Articles

Gut Microbiota Disruption in Hematologic Cancer Therapy: Molecular Insights and Implications for Treatment Efficacy.

Hematologic malignancies (HMs), including leukemia, lymphoma, and multiple myeloma, involve the uncontrolled proliferation of abnormal blood cells, posing significant clinical challenges due to their heterogeneity and varied treatment responses. Despite recent advancements in therapies that have improved survival rates, particularly in chronic lymphocytic leukemia and acute lymphoblastic leukemia, treatments like chemotherapy and stem cell transplantation often disrupt gut microbiota, which can negatively impact treatment outcomes and increase infection risks. This review explores the complex, bidirectional interactions between gut microbiota and cancer treatments in patients with HMs. Gut microbiota can influence drug metabolism through mechanisms such as the production of enzymes like bacterial β-glucuronidases, which can alter drug efficacy and toxicity. Moreover, microbial metabolites like short-chain fatty acids can modulate the host immune response, enhancing treatment effectiveness. However, therapy often reduces the diversity of beneficial bacteria, such as Bifidobacterium and Faecalibacterium, while increasing pathogenic bacteria like Enterococcus and Escherichia coli. These findings highlight the critical need to preserve microbiota diversity during treatment. Future research should focus on personalized microbiome-based therapies, including probiotics, prebiotics, and fecal microbiota transplantation, to improve outcomes and quality of life for patients with hematologic malignancies.

Cardiovascular disease and stroke following cancer and cancer treatment in older adults.

Cancer survivors can be at risk of cardiovascular disease (CVD) because of either their malignancy or its treatment. Although studies linking cancer and CVD exist, few examine risk in older adults, the impact of cancer treatment, or the effect of aspirin on reducing risk in this cohort. The authors conducted a secondary analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) trial to investigate the impact of cancer and cancer treatment on a composite CVD end point comprising hospitalization for heart failure (HHF), myocardial infarction (MI), and stroke. Of 15,454 Australian and US ASPREE participants, 1392 had an incident cancer diagnosis. Rates of CVD were greater in the cancer risk-set compared to the cancer-free risk-set (20.8 vs. 10.3 events per 1000 person-years; incidence rate ratio, 2.03; 95% confidence interval, 1.51-2.66), with increased incidence seen across MI, HHF, overall stroke, and ischemic stroke. Increased incidence remained after adjustment for clinically significant risk factors for CVD. Incidence was greatest in metastatic, hematological, and lung cancer. Chemotherapy was associated with increased risk of CVD. Similar rates of CVD were seen across aspirin and placebo groups. Incidence of CVD, including MI, HHF, and ischemic stroke, was increased in older adults with cancer. Aspirin did not impact CVD incidence. Risk may be higher in those with metastatic, hematological, and lung cancer, and following chemotherapy.

Influenza vaccine effectiveness in immunocompromised patients with cancer: A Danish nationwide register‐based cohort study

AbstractBackgroundInfluenza vaccination is free of charge for Danish citizens with acquired immunodeficiency but recommendations do not specifically target patients with cancer. This study investigated whether influenza vaccination reduces the main outcome of overall mortality and the secondary outcomes of influenza requiring treatment, pneumonia, myocardial infarction, stroke, heart failure, and venous thromboembolism in patients with cancer.MethodsThis was a register‐based nationwide cohort study. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95% CIs) for overall mortality and secondary outcomes were estimated using Cox proportional hazards models. Analyses were conducted separately for four subgroups: patients aged <65 years with solid tumors, patients aged ≥65 years with solid tumors, patients aged <65 years with hematological cancer, and patients aged ≥65 years with hematological cancer.ResultsA total of 53,249 adult patients with solid tumors who received chemotherapy and 22,182 adult patients with hematological cancer were followed for up to five influenza seasons in the study period of 2007–2018. In the main analysis covering December–March, influenza vaccination was associated with reduced overall mortality in all four subgroups. The reduction was most pronounced in patients with hematological cancer aged <65 years (aHR, 0.66; 95% CI, 0.51–0.87) and smallest in patients with solid tumors aged <65 years (aHR, 0.91; 95% CI, 0.84–0.99). In sensitivity analyses covering January–March, the aHR was 0.87 (95% CI, 0.65–1.16) in patients with hematological cancer aged <65 years and 1.01 (95% CI, 0.92–1.10) in patients with solid tumors aged <65 years. Results for the secondary outcomes were inconclusive.ConclusionsThe results of this study cannot reject that influenza vaccination reduces overall mortality in immunocompromised patients with cancer. The results must be interpreted with caution because of potential unmeasured confounding, which can result in the overestimation of influenza vaccine effectiveness.

Therapy-related myelodysplastic syndromes and acute myeloid leukemia

Progress always comes at a price: the field of oncology has seen unprecedented progress in treatment options recently for many solid and hematologic cancers. Unfortunately, these long-term survivors of prior cancer and cytotoxic therapy exposure are at higher risk of therapy-related myelodysplastic syndromes/acute myeloid leukemia (t-MDS/AML.) T-MDS/AML is a myeloid malignancy which occur after exposure to chemotherapy or radiation therapy for unrelated malignancy. T-MDS/AML is associated with adverse cytogenomic features and poor prognosis. While advances in the field of clonal hematopoiesis and germline variants has unraveled the molecular underpinnings of t-MDS/AML, we have miles to go in terms of t-MDS/AML directed therapy and improvement in outcomes. In this review, we discuss the epidemiology of t-MDS/AML, clinical and biological insights, evolution of t-MDS/AML and available treatment options.

Nanotechnology in Advancing Chimeric Antigen Receptor T Cell Therapy for Cancer Treatment.

Chimeric antigen receptor (CAR) T cell therapy has emerged as a groundbreaking treatment for hematological cancers, yet it faces significant hurdles, particularly regarding its efficacy in solid tumors and concerning associated adverse effects. This review provides a comprehensive analysis of the advancements and ongoing challenges in CAR-T therapy. We highlight the transformative potential of nanotechnology in enhancing CAR-T therapy by improving targeting precision, modulating the immune-suppressive tumor microenvironment, and overcoming physical barriers. Nanotechnology facilitates efficient CAR gene delivery into T cells, boosting transfection efficiency and potentially reducing therapy costs. Moreover, nanotechnology offers innovative solutions to mitigate cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cutting-edge nanotechnology platforms for real-time monitoring of CAR-T cell activity and cytokine release are also discussed. By integrating these advancements, we aim to provide valuable insights and pave the way for the next generation of CAR-T cell therapies to overcome current limitations and enhance therapeutic outcomes.

Regular whole blood donation and gastrointestinal, breast, colorectal and haematological cancer risk among blood donors in Australia

AbstractBackground and ObjectivesSeveral studies have suggested that blood donors have lower risk of gastrointestinal and breast cancers, whereas some have indicated an increased risk of haematological cancers. We examined these associations by appropriately adjusting the ‘healthy donor effect’ (HDE).Materials and MethodsWe examined the risk of gastrointestinal/colorectal, breast and haematological cancers in regular high‐frequency whole blood (WB) donors using the Sax Institute's 45 and Up Study data linked with blood donation and other health‐related data. We calculated 5‐year cancer risks, risk differences and risk ratios. To mitigate HDE, we used 5‐year qualification period to select the exposure groups, and applied statistical adjustments using inverse probability weighting, along with other advanced doubly robust g‐methods.ResultsWe identified 2867 (42.4%) as regular high‐frequency and 3888 (57.6%) as low‐frequency donors. The inverse probability weighted 5‐year risk difference between high and low‐frequency donors for gastrointestinal/colorectal cancer was 0.2% (95% CI, −0.1% to 0.5%) with a risk ratio of 1.25 (0.83–1.68). For breast cancer, the risk difference was −0.2% (−0.9% to 0.4%), with a risk ratio of 0.87 (0.48–1.26). Regarding haematological cancers, the risk difference was 0.0% (−0.3% to 0.5%) with a risk ratio of 0.97 (0.55–1.40). Our doubly robust estimators targeted minimum loss‐based estimator (TMLE) and sequentially doubly robust (SDR) estimator, yielded similar results, but none of the findings were statistically significant.ConclusionAfter applying methods to mitigate the HDE, we did not find any statistically significant differences in the risk of gastrointestinal/colorectal, breast and haematological cancers between regular high‐frequency and low‐frequency WB donors.

Characterising how a single bout of exercise in people with myeloma affects clonal plasma cell and immune effector cell frequency in blood, and daratumumab efficacy in vitro

Multiple myeloma is a haematological cancer characterised by the accumulation of clonal plasma cells in the bone marrow and is commonly treated with daratumumab, an anti-CD38 monoclonal antibody immunotherapy. Daratumumab often fails to induce stringent complete responses, due in part to resistance to antibody-dependent cellular cytotoxicity (ADCC) exerted by natural killer (NK)-cells and monocytes. Exercise bouts undertaken by healthy people induce lymphocytosis in blood, including to NK-cells and B-cells, but the effects of exercise are unknown in myeloma patients. In addition, whether exercise mobilises plasma cells has not been adequately investigated, and as such the potential impact of exercise on daratumumab treatment is unclear. In this exploratory pilot study, n = 16 smouldering multiple myeloma participants enrolled and n = 9 completed the study which comprised a bout of cycling 15% above anaerobic threshold for ∼30-min, with blood samples collected pre-, immediately post-, and 30-min post-exercise. Peripheral blood mononuclear cells were isolated from blood samples and incubated with the RPMI-8226 plasmacytoma cell line, with or without the presence of daratumumab to determine specific lysis using a calcein-release assay. Daratumumab-mediated cell lysis increased from 18.8% to 23.2% pre- to post-exercise, respectively (p < 0.001), owing to an increased frequency of CD3−CD56+CD16+ NK-cells (+348%), HLA-DR+CD14dimCD16+ monocytes (+125%), and HLA-DR+CD14+CD32+ monocytes (+41%) in blood (p < 0.01). However, overall, total plasma cells (CD38+CD138+) nor clonal plasma cells (CD38brightCD138+CD45−/dimCD19− with light-chain restriction) increased in blood (p > 0.05). Notably, we observed a 305% increase in NK-cells expressing CD38, the daratumumab target antigen, which might render NK-cells more susceptible to daratumumab-mediated fratricide – whereby NK-cells initiate ADCC against daratumumab-bound NK-cells. In conclusion, exercise modestly improved the efficacy of daratumumab-mediated ADCC in vitro. However, plasma cells were largely unchanged, and NK-cells expressing CD38 – the daratumumab target antigen – increased in blood. Future research should consider the optimal timings of exercise during daratumumab treatment in myeloma to avert exacerbation of daratumumab-mediated NK-cell lysis.

Chimeric Antigen Receptor T Cells Targeting CD19 and GCC in Metastatic Colorectal Cancer

Chimeric antigen receptor (CAR) T-cell therapy (CART) has transformed the treatment landscape of hematologic cancer, but has negligible effects for adult solid cancers. In this trial, an autologous CAR T-cell product demonstrated antitumor activity in heavily pretreated patients with metastatic colorectal cancer (mCRC). To evaluate the safety and efficacy of guanylate cyclase-C (GCC19) CART in participants with metastatic colorectal cancer (mCRC). This single-arm, nonrandomized, phase 1 trial was conducted at the First Hospital of Jilin University from December 3, 2020, to April 13, 2022. Data analysis was conducted from May 2022 to April 2024. Adults with relapsed and refractory mCRC expressing GCC were treated with GCC19CART, a mixture of autologous CAR T cells transduced with lentiviral vectors expressing genes that encode either CD-19 CAR or GCC CAR. Safety and tolerability of CAR T-cell therapy targeting GCC in patients with mCRC without therapeutic options is capable of conferring a reasonable likeliness of clinical benefit. Other outcomes included objective response rate, progression-free survival, overall survival, and immune activation. Of 15 patients 9 (60%) were women, and the median (range) age was 44 (33-61) years. Treatment with GCC19CART was associated with the development of cytokine release syndrome and diarrhea in most patients, all of which were self-limited and manageable. The objective response rate was 40%, with a partial response in 2 of 8 and 4 of 7 patients treated with either 1 × 106 cells/kg or 2 × 106 cells/kg. Median overall survival was 22.8 months (95% CI, 13.4-26.1) at data cutoff; the median progress-free survival was 6.0 months in the high dose level group (95% CI, 3.0 to not available). The results of this nonrandomized clinical trial suggest that GCC19CART was safe and tolerable in heavily pretreated patients with mCRC and is the first CAR T-cell therapy known to produce objective clinical activity in refractory cancer. Given the paucity of effective therapeutics developed for colorectal cancer in recent decades, the observation that CD-19 CART target engagement can robustly induce GCC19CART target engagement sufficient to produce objective activity may serve as a foundation to develop effective cellular therapy in mCRC and other solid cancers. Chinese Clinical Trial Registry: ChiCTR2000040645.

Use of Hematopoietic Cell Transplant for Hematologic Cancers by Race, Ethnicity, and Age.

Utilization of hematopoietic cell transplantation (HCT) for hematologic cancers previously demonstrated race, ethnicity, and age-based disparities. To evaluate utilization over time by race, ethnicity, and age to determine if disparities persist in light of recent significant increases in HCT volume. This US population-based retrospective cohort study includes patients who received transplants from January 2009 to December 2018. Data collection and cleaning occurred from February 2019 to November 2021, and data analysis occurred from January 2022 to October 2023. Method 1 restricted the analysis to Surveillance, Epidemiology and End Results (SEER) reporting areas for cases and transplants. Method 2 applied SEER age-, race-, and ethnicity-specific incidence rates to corresponding US census population and included all transplants reported to the Center for International Blood and Marrow Transplant Research. Race and ethnicity groups were hierarchically defined as Hispanic (any race), non-Hispanic White, non-Hispanic Black, and non-Hispanic Other (Asian and American Indian). Receipt of HCT. Utilization rate of autologous or allogeneic HCT for patients with hematologic cancers by age, race, and ethnicity. From 2009 to 2018, 136 280 HCTs were analyzed for 6 hematologic cancers comprising 16.7% pediatric/adolescent/young adults (0-39 years), 83.3% adults (40-84 years), 58% male, 10.3% Hispanic, 11.4% non-Hispanic Black, 3.8% non-Hispanic Other, and 74.5% non-Hispanic White patients, with 49 385 allogeneic and 86 895 autologous HCTs performed. HCT utilization increased over time for all disease, age, race, and ethnic groups. From 2017 to 2018, adult (40-84 years) allogeneic transplant utilization for acute myeloid leukemia and myelodysplastic syndrome (MDS) was similar for Hispanic and non-Hispanic White or Other patients but was lower for non-Hispanic Black patients (acute myeloid leukemia: 19% vs 13%; MDS: 9%-10% vs 5%). Similarly, autologous transplant utilization for lymphoma was similar for all race and ethnicity groups; however, autologous transplant for multiple myeloma was highest for non-Hispanic White patients and lower for all other groups (31% vs 26%-27%). In patients aged 0 to 39 years, utilization of allogeneic transplant for acute lymphoblastic leukemia was highest in Hispanic patients, followed by non-Hispanic White, Black, and Other races (acute lymphoblastic leukemia: 19%, 18%, 17%, and 16%, respectively). In this cohort study of autologous and allogeneic transplant utilization for hematologic cancers, disparities persisted for non-Hispanic Black patients. Hispanic, non-Hispanic Other, and younger age groups had increased utilization over time that was on par with non-Hispanic White patients in the most recent cohort.

The impact of cancer-related diarrhea on changes in cancer therapy.

The impact of cancer-related diarrhea (CRD) on changes in cancer therapy remains poorly characterized despite its prevalence. We performed a longitudinal observational study using IQVIA PharMetrics Plus claims data. Patients included adults with CRD identified by diagnosis codes or pharmacy claims and compared their outcomes to matched (1:1) patients without CRD. Treatment parameters (discontinuation, persistence, augmentation, dose titration, adherence) were evaluated and stratified for the first cancer therapy (chemotherapy vs. targeted therapy vs. both). A multivariate Cox proportional hazards model was used to estimate the difference in risk of each treatment parameter between cohorts, adjusting for cancer type, therapy, and comorbidities. We identified 104,135 matched pairs of patients with solid (n = 94,411) or hematologic cancers (n = 9,724) receiving chemotherapy (n = 47,220), targeted therapy (n = 2,427), or both (n = 5,313). Patients with CRD discontinued therapy more frequently than those without CRD (chemotherapy [81.5% vs. 62.3%], targeted therapy [69.2% vs. 64.3%], both [96.0% vs. 85.5%], p < 0.0001). The overall proportion of discontinuation was higher (82.4% vs. 64.6%, p < 0.0001), including a higher risk of discontinuation (HR = 1.40, p < 0.001) for patients with CRD. The mean time to discontinuation (59.6 ± 54.1 vs. 68.3 ± 76.6days), switch (72.0 ± 48.6 vs. 96.9 ± 84.0days), persistence (95.1 ± 98.1 vs. 154.3 ± 142.7days), and adherence (25.5% ± 37.2 vs. 47.9 ± 41%) were all lower (p < 0.0001) among patients with CRD. Patients who develop CRD undergo significant and clinically impactful index treatment discontinuation, treatment switching, and have lower adherence and persistence of anticancer therapy compared to patients without CRD. Strategies to control CRD to optimize cancer therapy are urgently needed.

Dual CAR-T cell therapy for glioblastoma: strategies to cure tumour diseases based on a mathematical model

AbstractThe CAR-T cell immunotherapy entails the genetic reprogramming of T-lymphocytes, which then engage with cancer cells, triggering an anti-tumour immune response. While this treatment has gained approval for hematological cancers, addressing solid tumours presents new obstacles. Challenges include the heterogeneity of antigen expression within solid tumours, encompassing antigen-positive non-tumoural cells, the presence of immune inhibitory molecules, and the difficulty of CAR-T cell trafficking within the tumour microenvironment. In this article, we analytically study a generalisation of a mathematical model proposed by León-Triana et al. (Cancers 13(4):703, 2021a. https://doi.org/10.3390/cancers13040703, Commun Nonlinear Sci Numer Simul 94:105570). This model focuses on the dynamics of glioblastoma, the most aggressive brain tumour, and its response to CAR-T cell treatment. We study the basic properties of the model, the dynamics of the solutions of the model when the treatment is not sustained during the time, and finally we study analytically the model when the therapy is constant, periodic and/or impulsive. We derive sufficient conditions for global stability of tumour-free equilibrium, as well as necessary and sufficient conditions for local stability of the equilibrium obtaining conditions for an effective treatment. Finally, we perform different numerical simulations to find the strategies to keep the tumour under control. The obtained results are based on a combination of different analytical techniques in differential equations, dynamical systems and numerical simulations.

In Vivo Monitoring and Magnetically‐Enhanced Delivery of CAR T‐Cells to Solid Tumor

AbstractChimeric antigen receptor (CAR) T‐cell therapy demonstrates efficacy for the treatment of hematologic cancers, but remains challenging in solid tumors because of the hostile tumor microenvironment and heterogeneity that restrict the infiltration and activity of CAR T‐cells. The lack of clinical imaging methods to monitor CAR T‐cell therapy in patients limits the potential to enhance the therapeutic approach and predict patient response. Here, a straightforward, non‐invasive method for Magnetic Resonance Imaging (MRI) tracking and magnetic targeting of CAR T‐cells to enhance T‐cell trafficking to solid tumors, in a setting that can be deployed in clinics, is reported. Iron oxide nanoparticles are loaded into T‐cells, allowing MRI detection and magnetic cell guidance, while preserving T‐cell viability, functions, and CAR specificity to target epidermal growth factor receptor (EGFR)‐expressing tumors. Longitudinal MRI monitoring of T‐cells over 14 days reveals differences in tumor infiltration rates and antitumor efficacy between EGFR‐targeted CAR T‐cells and non‐transduced T‐cell. Moreover, an external magnet placed over the tumor enhances the infiltration of CAR T‐cells and increases their antitumor effect. MRI monitoring and magnetic guidance represent a dual‐pronged clinically feasible therapeutic strategy to control and promote CAR T‐cells delivery into solid tumors, thereby improving the precision, efficacy, and safety of the treatment.

Enhancing Fc-mediated effector functions of monoclonal antibodies: The example of HexaBodies.

Since the approval of the CD20-targeting monoclonal antibody (mAb) rituximab for the treatment of lymphoma in 1997, mAb therapy has significantly transformed cancer treatment. With over 90 FDA-approved mAbs for the treatment of various hematological and solid cancers, modern cancer treatment relies heavily on these therapies. The overwhelming success of mAbs as cancer therapeutics is attributed to their broad applicability, high safety profile, and precise targeting of cancer-associated surface antigens. Furthermore, mAbs can induce various anti-tumor cytotoxic effector mechanisms including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC), all of which are mediated via their fragment crystallizable (Fc) domain. Over the past decades, these effector mechanisms have been substantially improved through Fc domain engineering. In this review, we will outline the different approaches to enhance Fc effector functions via Fc engineering of mAbs, with a specific emphasis on the so-called "HexaBody" technology, which is designed to enhance the hexamerization of mAbs on the target cell surface, thereby inducing greater complement activation, CDC, and receptor clustering. The review will summarize the development, preclinical, and clinical testing of several HexaBodies designed for the treatment of B-cell malignancies, as well as the potential use of the HexaBody technology beyond Fc-mediated effector functions.

Research progress in targeting GPRC5D for the treatment of multiple myeloma

Multiple myeloma (MM) is a malignant disease caused by the abnormal clonal proliferation of plasma cells, accounting for 10% of all hematologic cancers. In recent years, with the development and application of targeted drugs, a significant progress has been observed in the treatment methods of MM, but patients still face the challenges of relapse and drug resistance. Moreover, G protein-coupled receptor class C Group 5 member D (GPRC5D) is highly expressed in MM cells independently of B cell maturation antigen (BCMA) and is a highly promising target following BCMA. Aside from emphasizing the therapeutic efficacy and safety of targeting GPRC5D for the treatment of MM, this study also provides a prospective view on the mechanisms of drug resistance and relapse associated with GPRC5D-targeted therapies, as well as the timing of sequential or combined treatment strategies involving the dual targeting of both GPRC5D and BCMA.

B - 105 ICANS, CAR-T, and Cognition: a Case Study

Abstract Objective Immune effector cell-associated neurotoxicity syndrome (ICANS), an autoimmune delirious condition, affects 37.5% to 77% of individuals during or after chimeric antigen receptor T-cell (CAR-T) treatment for hematologic cancers (Grant et al., 2022). Initial clinical response varies widely but may include apraxia, aphasia, disorientation, and hallucinations (Möhn et al., 2022). Recent research indicates complete symptom resolution in most patients a month post-ICANS onset (Sales et al., 2023). However, a self-report study suggested more than 1 in 3 report persisting cognitive sequelae 1–5 years post-ICANS onset (Rurak et al., 2020). This discrepancy may be due to subtle changes missed by the Montreal Cognitive Objective Assessment (Sales et al., 2023; Möhn et al., 2022). The current case report investigates neurobehavioral outcome post-ICANS via comprehensive neuropsychological assessment. Method Two weeks post-CAR-T therapy, a 53-year-old male exhibited abrupt onset facial palsy and cognitive slowing prompting hospitalization. His wife reported new-onset apathy, atypical behaviors exacerbation (e.g., licking plate), and cognitive lapses (e.g., short-term memory, slowing, repeating questions) with little insight. Neuroimaging revealed supratentorial white matter hyperintensities plus calvarium and R skull base enhancing lesion regression. Results Neuropsychological assessment 10-months post-ICANS revealed subtle executive inefficiencies with family reports of improved yet ongoing social disinhibition and apathy. Conclusions This is the first comprehensive neuropsychological assessment of a patient who developed ICANS post-CAR-T therapy. Neuropsychologists should be aware of delayed cognitive sequelae possibility of this advancing treatment option. Future studies will be useful for patient/family preparation.

MCMC Methods for Parameter Estimation in ODE Systems for CAR-T Cell Cancer Therapy.

Chimeric antigen receptor (CAR)-T cell therapy represents a breakthrough in treating resistant hematologic cancers. It is based on genetically modifying T cells transferred from the patient or a donor. Although its implementation has increased over the last few years, CAR-T has many challenges to be addressed, for instance, the associated severe toxicities, such as cytokine release syndrome. To model CAR-T cell dynamics, focusing on their proliferation and cytotoxic activity, we developed a mathematical framework using ordinary differential equations (ODEs) with Bayesian parameter estimation. Bayesian statistics were used to estimate model parameters through Monte Carlo integration, Bayesian inference, and Markov chain Monte Carlo (MCMC) methods. This paper explores MCMC methods, including the Metropolis-Hastings algorithm and DEMetropolis and DEMetropolisZ algorithms, which integrate differential evolution to enhance convergence rates. The theoretical findings and algorithms were validated using Python and Jupyter Notebooks. A real medical dataset of CAR-T cell therapy was analyzed, employing optimization algorithms to fit the mathematical model to the data, with the PyMC library facilitating Bayesian analysis. The results demonstrated that our model accurately captured the key dynamics of CAR-T cell therapy. This conclusion underscores the potential of parameter estimation to improve the understanding and effectiveness of CAR-T cell therapy in clinical settings.

Promising Therapeutic Strategies for Hematologic Malignancies: Innovations and Potential.

In this review we explore innovative approaches in the treatment of hematologic cancers by combining various therapeutic modalities. We discuss the synergistic potential of combining inhibitors targeting different cellular pathways with immunotherapies, molecular therapies, and hormonal therapies. Examples include combining PI3K inhibitors with proteasome inhibitors, NF-κB inhibitors with immunotherapy checkpoint inhibitors, and neddylation inhibitors with therapies targeting the tumor microenvironment. Additionally, we discuss the potential use of small molecules and peptide inhibitors in hematologic cancer treatment. These multidimensional therapeutic combinations present promising strategies for enhancing treatment efficacy and overcoming resistance mechanisms. However, further clinical research is required to validate their effectiveness and safety profiles in hematologic cancer patients.

Abstract B053: Tumor-associated macrophages diminishes IL1RAP-targeting CAR-T cell therapy efficacy in Ewing sarcoma

Abstract Ewing sarcoma (EwS) is a pediatric malignancy of soft tissue and bone with a poor prognosis, especially in its metastatic stages. We have previously identified IL1RAP as a promising target for immunotherapies like chimeric antigen receptor (CAR) T cell therapy against EwS. However, CAR-T cells, despite their success in hematological cancers, often show limited efficacy against solid tumors. In orthotopic xenograft models of Ewing sarcoma (EwS) we have observed that CD11b+ CD206+ macrophages, known as tumor-associated macrophages (TAMs), surround the primary tumor. Treatment with IL1RAP-targeting CAR-T cells specific to EwS results in T cells localizing with these macrophages and failing to infiltrate the primary tumor. This study aims to characterize the impact of TAMs on CAR-T cell efficacy in EwS. We hypothesized that TAMs, polarized by Ewing sarcoma cells, suppress IL1RAP CAR-T cell activity. To model these interactions, we co-cultured EwS cells, macrophages, and CAR-T cells, performing luciferin-based in vitro cytotoxicity assays. THP-1 monocytes were differentiated into macrophages and polarized into M1 or M2 states using cytokines (LPS + IFN-y, IL-4 + IL-13), or differentiated into TAMs by co-culture with EwS cell lines. In vitro cytotoxicity assays were conducted using luciferase-expressing EwS target cells, polarized THP-1 macrophages, and IL1RAP CAR-T effector cells, with luminescence indicating EwS cell survival. We found that M1 macrophages did not affect CAR-T cell targeting of EwS cells, whereas M2 macrophages and TAMs significantly decreased specific lysis (p &amp;lt; 0.001). Conditioned media from polarized macrophages had no effect on CAR-T cell performance against EwS, suggesting that physical proximity or direct contact with TAMs is necessary to suppress CAR-T cell function. Western blot analysis of polarized THP-1 macrophages revealed that M2-polarized macrophages upregulated IL1RAP expression compared to M1 macrophages. Ongoing experiments aim to determine whether elevated IL1RAP expression in M2 macrophages redirects IL1RAP CAR-T cells away from EwS cells or if M2 macrophages mediate general suppression of CAR-T cell activity. Additionally, we are investigating whether THP-1-derived TAMs and primary macrophages also upregulate IL1RAP expression when polarized and how this affects syngeneic CAR-T cell performance. Our findings indicate that TAMs can influence the efficacy of IL1RAP-targeting CAR-T cells against EwS. Further investigation into the specific mechanisms responsible for this suppressive effect could enhance CAR-T therapy for Ewing sarcoma and potentially other solid tumors. Citation Format: Yue Zhou (Joe) Huang, Melanie Rouleu, Poul Sorensen. Tumor-associated macrophages diminishes IL1RAP-targeting CAR-T cell therapy efficacy in Ewing sarcoma [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B053.

Predicting place of death of patients with advanced cancer receiving home-based palliative care services in Iran

BackgroundWhile home is frequently expressed as the favorite place of death (PoD) among terminally ill cancer patients, various factors affect the fulfillment of this wish. The determinants of the PoD of cancer patients in countries without healthcare system-integrated palliative and supportive care have not been studied before. This study aimed at identifying the predictors of the PoD of patients who suffer from advanced cancer by developing a reliable predictive model among who received home-based palliative care in Iran as a representative of the countries with isolated provision of palliative care services.MethodsIn a cross-sectional study, electronic records of 4083 advanced cancer patients enrolled in the Iranian Cancer Control Center (MACSA) palliative homecare program, who died between February 2018 and February 2020 were retrieved. Multivariable binary logistic regression analysis as well as subgroup analyses (location, sex, marital status, and tumor topography) was performed to identify the predictors of PoD.ResultsOf the 2398 cases included (mean age (SD) = 64.17 (14.45) year, 1269 (%52.9) male), 1216 (50.7%) patients died at home. Older age, presence and intensity of medical homecare in the last two weeks and registration in the Tehran site of the program were associated with dying at home (P < 0.05). Gynecological or hematological cancers, presence and intensity of the calls received from the remote palliative care unit in the last two weeks were predictors of death at the hospital (p < 0.05). The model was internally and externally validated (AUC = 0.723 (95% CI = 0.702–0.745; P < 0.001) and AUC = 0.697 (95% CI = 0.631–0.763; P < 0.001) respectively).ConclusionOur model highlights the demographic, illness-related and environmental determinants of the PoD in communities with patchy provision of palliative care. It also urges policymakers and service providers to identify and take the local determinant of the place of death into account to match the goals of palliative and supportive services with the patient preferences.

Adopting prospective antimicrobial stewardship (AMS) practice in high-risk immunosuppressed groups: an urgent call to action in the era of antimicrobial resistance (AMR).

Life-saving immunosuppressive treatments including intensive chemotherapy and bone marrow transplantation expose patients to a considerable risk of death from infection globally. With evolving AMR and transmission, this could spell disaster for patients across the world and society at large. Antimicrobial stewardship (AMS) and prompt appropriate management of potentially fatal, emergent infections are essential. It is now apparent that antibacterial prophylaxis in patients with haematological cancer may not provide survival benefit while simultaneously increasing risks for AMR carriage. With evolving AMR and increasing immunosuppressed populations across the world, we must institute robust AMS practices. Significant resources are used to combat the impact of AMR on immunosuppressed patients. For lower-middle income countries (LMICs) these resources may not be available and as such the impact caused by AMR is greater. By considering the patient journey holistically we consider risk of infection presented to patients temporally and geographically. A short-term and easy to implement approach of multi-disciplinary team (MDT)-style advance care planning for infection is advocated. Antimicrobials, when used appropriately, enable healthcare procedures to occur and exist. Indeed, the very future of clinical medicine will rely on this yet to be realized value of enablement. Proactive effort and change must occur across all sectors with holism; hence our impetus for convening a joint industry and clinical working group. With at-risk immunosuppressed groups being a sentinel for change, awareness and implementation of patient-centric actions for infection are essential and our recommendations serve as an urgent call to action.