Antigen Receptor Research Articles

Association of CD19+-targeted chimeric antigen receptor (CAR) T-cell therapy with hypogammaglobulinemia, infection, and mortality

BackgroundCD19-targeted chimeric antigen receptor T-cell therapy (CAR-T therapy) has revolutionized the treatment of hematologic malignancies. As these cells target CD19+ receptors on B-cells, there is the potential for B-cell aplasia and hypogammaglobulinemia. Data on the degree and clinical significance of hypogammaglobulinemia are sparse. ObjectiveTo evaluate hypogammaglobulinemia after CD19-targeted CAR-T therapy and risk factors for hypogammaglobulinemia, infections, and mortality. MethodsWe performed a retrospective evaluation of 579 patients receiving CD19-directed CAR-T therapy and evaluated demographics, hypogammaglobulinemia (immunoglobulin G [IgG]≤600mg/dL), infections pre- and post-CAR-T therapy, and risk factors for hypogammaglobulinemia, infection, hospitalizations, and mortality. ResultsPatients had a mean age of 64 years and 64% were male. Prior to CAR-T therapy, 60% of patients had hypogammaglobulinemia, which increased to 91% post-CAR-T therapy. Mean IgG levels decreased from pre- to post-CAR-T therapy (587 to 362 mg/dL; p<0.0001). 37% of patients developed a serious infection post-CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was associated with worsening hypogammaglobulinemia post-CAR-T therapy. Hypogammaglobulinemia post-CAR-T therapy was associated with an increased risk of serious infection post-CAR-T therapy (IRR=2.7; 95% CI=1.5-5.2; p=0.002). Risk factors for mortality included mild hypogammaglobulinemia (400mg/dL<IgG≤600mg/dL), infections ≤100 days post-CAR-T therapy, and hospitalizations for infections. Immunoglobulin replacement was associated with a decreased risk of mortality. ConclusionsWe identified ∼90% of patients with hypogammaglobulinemia after CAR-T therapy. Hypogammaglobulinemia pre-CAR-T therapy was strongly predictive of worsening hypogammaglobulinemia post-CAR-T therapy, which was associated with an increased risk of serious infection and mortality post-CAR-T therapy. Increased immunological monitoring is needed to identify high-risk patients who may benefit from interventions to decrease morbidity and mortality.

Long-term safety and efficacy of the fully human CAR-T therapy CT103A in relapsed/refractory multiple myeloma

CT103A is a fully human chimeric antigen receptor T-cell (CAR-T) product for targeting B-cell maturation antigen (BCMA). This study presents the updated safety and efficacy profiles of CT103A in patients with relapsed/refractory multiple myeloma (RRMM) after long-term follow-up. As of July 31, 2023, the median follow-up time after CAR-T-cell infusion was 45.0 months (range, 0.7-58.3 months). During long-term follow-up, the incidence of adverse events gradually decreased over time. One patient had a maximum duration of response of nearly five years. All 18 patients (100%) achieved partial remission or better; 77.8% (14 of 18) of patients eventually exhibited complete response (CR) or stringent complete response (sCR), with response increasing over time. At the time of data cut-off, nine patients were still alive, and seven patients had an sCR status with negative minimal residual disease (MRD). The median progression-free survival (PFS) was 22.6 months, and the median overall survival (OS) was 50.2 months for all 18 patients. The median CAR transgene persistence was 14.0 months (range, 0.7-57.3 months). Long-term follow-up demonstrated that CT103A confers durable clinical benefit for RRMM patients based on the sustained presence of fully human CAR-T cells.

Loss of p53 Impairs Death Receptor Expression and Confers Resistance to CD19 CAR T Cell Therapy in BCP-ALL

Loss of p53 function predicts a dismal outcome in relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Chimeric antigen receptor T cell (CAR T) therapy was recently approved to salvage relapsed/refractory BCP-ALL. We observed a significantly worse overall survival after CD19-targeting CAR T therapy in children with TP53-mutated (TP53Mut) compared to TP53-wildtype (TP53WT) BCP-ALL. To investigate the effect of p53 loss on CAR T therapy response, we modelled TP53 mutations in two BCP-ALL cell lines and observed resistance to CAR T upon p53 loss. Moreover, expression analysis in cell lines and xenografts demonstrated that loss of p53 abrogates expression of the death receptors Fas and DR5, both implicated in CAR T cytotoxicity. Conversely, ectopic expression of Fas improved CAR T cytotoxicity. Furthermore, p53 stabilization induced expression of both Fas and DR5, accompanied by increased CAR T-mediated killing. While these findings provide mechanistic insight as to why CAR T therapy fails against TP53Mut BCP-ALL, they may also provide opportunities to enhance the efficacy of CAR T treatment both in patients with TP53Mut and TP53WT BCP-ALL. Furthermore, these data underscore the need of alternative curative therapies for this very high-risk patient group.

Safety in Subsequent Lines of Therapy in Patients With Relapsed Refractory Follicular Lymphoma

Follicular lymphoma (FL) is a disease often characterized by chronic and successive relapses after first-line chemoimmunotherapy. Although chemoimmunotherapy and combination therapy, such as lenalidomide with rituximab, are well established in the treatment sequence of FL, there is a need to streamline treatment options and determine placement of novel agents, such as chimeric antigen receptor T-cell therapy, an enhancer of zeste homolog 2 inhibitor, or a phosphoinositide 3 kinase inhibitor, into the treatment landscape. As such, the purpose of this review is to compare the safety profiles of approved agents in subsequent lines of therapy for relapsed or refractory FL and to assess how the management of adverse events may impact treatment choice.

Inhibition of Cbl-b restores effector functions of human intratumoral NK cells

BackgroundT cell-based immunotherapies including immune checkpoint blockade and chimeric antigen receptor T cells can induce durable responses in patients with cancer. However, clinical efficacy is limited due to the ability of cancer cells to evade immune surveillance. While T cells have been the primary focus of immunotherapy, recent research has highlighted the importance of natural killer (NK) cells in directly recognizing and eliminating tumor cells and playing a key role in the set-up of an effective adaptive immune response. The remarkable potential of NK cells for cancer immunotherapy is demonstrated by their ability to broadly identify stressed cells, irrespective of the presence of neoantigens, and their ability to fight tumors that have lost their major histocompatibility complex class I (MHC I) expression due to acquired resistance mechanisms.However, like T cells, NK cells can become dysfunctional within the tumor microenvironment. Strategies to enhance and reinvigorate NK cell activity hold potential for bolstering cancer immunotherapy.MethodsIn this study, we conducted a high-throughput screen to identify molecules that could enhance primary human NK cell function. After compound validation, we investigated the effect of the top performing compounds on dysfunctional NK cells that were generated by a newly developed in vitro platform. Functional activity of NK cells was investigated using compounds alone and in combination with checkpoint inhibitor blockade. The findings were validated on patient-derived intratumoral dysfunctional NK cells from different cancer types.ResultsThe screening approach led to the identification of a Casitas B-lineage lymphoma (Cbl-b) inhibitor enhancing the activity of primary human NK cells. Furthermore, the Cbl-b inhibitor was able to reinvigorate the activity of in vitro generated and patient-derived dysfunctional NK cells. Finally, Cbl-b inhibition combined with T-cell immunoreceptor with Ig and ITIM domains (TIGIT) blockade further increased the cytotoxic potential and reinvigoration of both in vitro generated and patient-derived intratumoral dysfunctional NK cells.ConclusionsThese findings underscore the relevance of Cbl-b inhibition in overcoming NK cell dysfunctionality with the potential to complement existing immunotherapies and improve outcomes for patients with cancer.

Formin-like 1β phosphorylation at S1086 is necessary for secretory polarized traffic of exosomes at the immune synapse in Jurkat T lymphocytes

We analyzed here how formin-like 1 β (FMNL1β), an actin cytoskeleton-regulatory protein, regulates microtubule-organizing center (MTOC) and multivesicular bodies (MVB) polarization and exosome secretion at an immune synapse (IS) model in a phosphorylation-dependent manner. IS formation was associated with transient recruitment of FMNL1β to the IS, which was independent of protein kinase C δ (PKCδ). Simultaneous RNA interference of all FMNL1 isoforms prevented MTOC/MVB polarization and exosome secretion, which were restored by FMNL1βWT expression. However, expression of the non-phosphorylatable mutant FMNL1βS1086A did not restore neither MTOC/MVB polarization nor exosome secretion to control levels, supporting the crucial role of S1086 phosphorylation in MTOC/MVB polarization and exosome secretion. In contrast, the phosphomimetic mutant, FMNL1βS1086D, restored MTOC/MVB polarization and exosome secretion. Conversely, FMNL1βS1086D mutant did not recover the deficient MTOC/MVB polarization occurring in PKCδ-interfered clones, indicating that S1086 FMNL1β phosphorylation alone is not sufficient for MTOC/MVB polarization and exosome secretion. FMNL1 interference inhibited the depletion of F-actin at the central region of the immune synapse (cIS), which is necessary for MTOC/MVB polarization. FMNL1βWT and FMNL1βS1086D, but not FMNL1βS1086A expression, restored F-actin depletion at the cIS. Thus, actin cytoskeleton reorganization at the IS underlies the effects of all these FMNL1β variants on polarized secretory traffic. FMNL1 was found in the IS made by primary T lymphocytes, both in T cell receptor (TCR) and chimeric antigen receptor (CAR)-evoked synapses. Taken together, these results point out a crucial role of S1086 phosphorylation in FMNL1β activation, leading to cortical actin reorganization and subsequent control of MTOC/MVB polarization and exosome secretion.

Formin-like 1β phosphorylation at S1086 is necessary for secretory polarized traffic of exosomes at the immune synapse in Jurkat T lymphocytes.

We analyzed here how formin-like 1 β (FMNL1β), an actin cytoskeleton-regulatory protein, regulates microtubule-organizing center (MTOC) and multivesicular bodies (MVB) polarization and exosome secretion at an immune synapse (IS) model in a phosphorylation-dependent manner. IS formation was associated with transient recruitment of FMNL1β to the IS, which was independent of protein kinase C δ (PKCδ). Simultaneous RNA interference of all FMNL1 isoforms prevented MTOC/MVB polarization and exosome secretion, which were restored by FMNL1βWT expression. However, expression of the non-phosphorylatable mutant FMNL1βS1086A did not restore neither MTOC/MVB polarization nor exosome secretion to control levels, supporting the crucial role of S1086 phosphorylation in MTOC/MVB polarization and exosome secretion. In contrast, the phosphomimetic mutant, FMNL1βS1086D, restored MTOC/MVB polarization and exosome secretion. Conversely, FMNL1βS1086D mutant did not recover the deficient MTOC/MVB polarization occurring in PKCδ-interfered clones, indicating that S1086 FMNL1β phosphorylation alone is not sufficient for MTOC/MVB polarization and exosome secretion. FMNL1 interference inhibited the depletion of F-actin at the central region of the immune synapse (cIS), which is necessary for MTOC/MVB polarization. FMNL1βWT and FMNL1βS1086D, but not FMNL1βS1086A expression, restored F-actin depletion at the cIS. Thus, actin cytoskeleton reorganization at the IS underlies the effects of all these FMNL1β variants on polarized secretory traffic. FMNL1 was found in the IS made by primary T lymphocytes, both in T cell receptor (TCR) and chimeric antigen receptor (CAR)-evoked synapses. Taken together, these results point out a crucial role of S1086 phosphorylation in FMNL1β activation, leading to cortical actin reorganization and subsequent control of MTOC/MVB polarization and exosome secretion.

Outcomes of children and young adults with B-cell acute lymphoblastic leukemia given blinatumomab as last consolidation treatment before allogeneic hematopoietic stem cell transplantation.

Blinatumomab has remarkable efficacy in patients with relapsed/refractory (r/r) or measurable residual disease (MRD)-positive B-cell acute lymphoblastic leukemia (B-ALL). In many patients, blinatumomab treatment is followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, the influence of blinatumomab on HSCT outcomes in children and young adults (YA) remains to be fully elucidated. We conducted a single-center, retrospective analysis on patients given blinatumomab as last treatment before HSCT. Seventy-eight pediatric and YA patients were evaluated. With a median follow-up of 23.23 months, the 2-year disease-free (DFS) and overall survival (OS) probability were 72.2% and 89.2%, respectively, with a 2-year cumulative incidence (CI) of non-relapse mortality (NRM) of 2.6%. A trend toward improved 2-year DFS, but not OS, was noted in patients transplanted in first complete remission (CR1) (92.9%) compared to those in second or greater remission (CR2/3) (68.5%, p=0.18) due to a lower CI of relapse (0% vs. 29.9%, p=0.05). Among CR2/3 patients, those receiving the sequential combination of inotuzumab and blinatumomab had a significantly lower CI of relapse as compared to those who did not receive inotuzumab (9.5% vs. 40.4%, p=0.023). Relapse after HSCT occurred in 16 patients, all exhibiting CD19-positive blasts; 10 of them received anti-CD19 chimeric antigen receptor T-cell (CAR-T) therapy and 2 inotuzumab as salvage therapy, leading to a 2-year post-relapse OS of 52.7%. Our results indicate that HSCT following blinatumomab in children and YA with B-ALL is highly effective, being associated with low NRM and not affecting the efficacy of subsequent salvage immunotherapies, including CAR-T cells.

Chimeric Antigen Receptor T Cells for the Treatment of Multiple Myeloma.

Multiple myeloma (MM), characterized by abnormal proliferation of clonal plasma cells, is an incurable hematological malignancy. Various immunotherapy strategies have emerged as an efficacious approach for the treatment of MM, including monoclonal antibodies, antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cells. Anti-B-cell maturation antigen (BCMA) CAR-T cells have revolutionized the treatment of MM patients with relapsed/refractory disease and their clinical use was approved for the treatment of these patients. Despite this progress, the efficacy of CAR-T cells in MM is limited by the responsiveness of only a part of the treated patients, the relapse of other patients, the cost of the treatment and the diminished response in patients with prior exposure to anti-BCMA targeting agents. Ongoing clinical trials are evaluating the use of CAR-T cells at an earlier stage of MM disease and the use of CAR-T cells targeting other membrane antigens expressed on malignant plasma cells.

Identification and analysis of microplastic aggregation in CAR-T cells

Microplastics (MPs) are increasingly recognized as contaminants present in various environments and are widely acknowledged as potential hazards to the mammalian immune system. In our study of chimeric antigen receptor T cell (CAR-T) therapy, we observed the presence of MP in CAR-T cell products for the first time. It is worth exploring whether MP could enter CAR-T cells and how they might affect CAR-T cells’ functionality. Therefore, we analyzed how MP affected CD19 and BCMA-CAR-T cells. Based on flow cytometry, ELISA, and cytotoxicity analysis of in vitro and in vivo experiments, MP suppressed the activity of CAR-T cells. Subsequent investigation revealed that the exposure of CAR-T cells to varying concentrations of MP resulted in a notable increase in apoptosis, ferroptosis, and exhaustion levels. Furthermore, the hyperactivation of the mTOR signaling pathway in MP-treated CAR-T cells was verified. The partial restoration of CAR-T cell function in MP was achieved by inhibiting the mTOR pathway. MP present a threat to CAR-T cell function due to their role in inducing CAR-T cell apoptosis, ferroptosis, and T-cell exhaustion through the hyperactivation of mTOR signaling pathways.

Health-related quality of life dynamics: modeling insights from immunotherapy.

Understanding health-related quality of life (HRQoL) dynamics is essential for assessing and improving treatment experiences; however, clinical and observational studies struggle to capture their full complexity. We use simulation modeling and the case of Chimeric Antigen Receptor T-cell therapy-a type of cancer immunotherapy that can prolong survival, but carries life-threatening risks-to study HRQoL dynamics. We developed an exploratory system dynamics model with mathematical equations and parameter values informed by literature and expert insights.We refined its feedback structure and evaluated its dynamic behavior through iterative interviews. Model simulated HRQoL from treatment approval through six months post-infusion. Two strategies-reducing the delay to infusion and enhancing social support-were incorporated into the model. To dynamically evaluate the effect of these strategies, we developed four metrics: post-treatment HRQoL decline, recovery time to pre-treatment HRQoL, post-treatment HRQoL peak, and durability of the peak. Model captures key interactions within HRQoL, providing a nuanced analysis of its continuous temporal dynamics, particularly physical well-being, psychological well-being, tumor burden, receipt and efficacy of treatment, side effects, and their management. Model analysis shows reducing infusion delays enhanced HRQoL across all four metrics. While enhanced social support improved the first three metrics for patients who received treatment, it did not change durability of the peak. Simulation modeling can help explore the effects of strategies on HRQoL while also demonstrating the dynamic interactions between its key components, offering a powerful tool to investigate aspects of HRQoL that are difficult to assess in real-world settings.

Optimizing CAR-NK Cell Transduction and Expansion: Leveraging Cytokine Modulation for Enhanced Performance.

Cellular immunotherapy has emerged as one of the most potent approaches to treating cancer patients. Adoptive transfer of chimeric antigen receptor (CAR) T cells as well as the use of haploidentical natural killer (NK) cells can induce remission in patients with lymphoma and leukemia. Although the use of CAR T cells has been established, this approach is currently limited for wider use by the risk of severe adverse events, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Moreover, the risk of triggering graft vs host reactions in settings of allogeneic T cell infusion limits the use to autologous CAR T cells if advanced CRISPR engineering is not applied. In contrast, NK cell-based cancer immunotherapy has emerged as a safe approach even in allogeneic settings. However, efficient transduction of primary blood NK cells with vesicular stomatitis virus G glycoprotein (VSV-G) pseudotyped lentivirus commonly used for T cell modification remains challenging. This article presents a detailed method that significantly enhances the transduction efficiency of NK cells by utilizing a short-term culture in cytokine-supplemented medium. It also encompasses the preparation of high-titer and high-quality lentiviral particles for optimal NK cell transduction. Overall, this protocol details the step-by-step culture of NK cells in cytokine-supplemented medium, their transduction with VSV-G lentiviral vectors, and subsequent expansion for functional assays. © 2024 Wiley Periodicals LLC. Basic Protocol 1: Isolation of NK cells from human peripheral blood mononuclear cells (PBMCs) Basic Protocol 2: NK cell expansion and transduction with lentivirus for generating CAR-NK cells Support Protocol 1: Plasmid amplification Support Protocol 2: Lentivirus preparation Support Protocol 3: Lentivirus titration.

Oncolytic virus and CAR-T cell therapy in solid tumors.

Adoptive immunotherapy with T cells, genetically modified to express a tumor-reactive chimeric antigen receptor (CAR), is an innovative and rapidly developing life-saving treatment for cancer patients without other therapeutic opportunities. CAR-T cell therapy has proven effective only in hematological malignancies. However, although by now only a few clinical trials had promising outcomes, we predict that CAR-T therapy will eventually become an established treatment for several solid tumors. Oncolytic viruses (OVs) can selectively replicate in and kill cancer cells without harming healthy cells. They can stimulate an immune response against the tumor, because OVs potentially stimulate adaptive immunity and innate components of the host immune system. Using CAR-T cells along with oncolytic viruses may enhance the efficacy of CAR-T cell therapy in destroying solid tumors by increasing the tumor penetrance of T cells and reducing the immune suppression by the tumor microenvironment. This review describes recent advances in the design of oncolytic viruses and CAR-T cells while providing an overview of the potential combination of oncolytic virotherapy with CAR-T cells for solid cancers. In this review, we will focus on the host-virus interaction in the tumor microenvironment to reverse local immunosuppression and to develop CAR-T cell effector function.

Emerging Frontiers in Cancer Immunotherapy: Recent Advances in CAR-NK Cell and CAR-Macrophage Therapies

Chimeric antigen receptor (CAR) cell therapies have revolutionized the field of cancer treatment with the breakthrough successes of CAR-T cell therapy in hematological malignancies. However, CAR-T cell efficacy in solid tumors has been limited by challenges such as the immunosuppressive tumor microenvironment (TME) and safety concerns like cytokine release syndrome (CRS) and graft-versus-host disease (GvHD). This review focuses on the latest advancements in CAR-NK cell and CAR-macrophage therapies, which offer potential solutions to these limitations. CAR-NK cells exhibit natural cytotoxicity and MHC-independent tumor targeting, providing a safer profile with lower risks of GvHD and CRS compared to CAR-T cells. Innovations in CAR-NK cell therapy includes structural optimizations, gene editing with CRISPR-Cas9, and the development of multispecific CARs, all contributing to enhanced anti-tumor efficacy, especially in solid tumors. Meanwhile, CAR-macrophages are effective in remodeling the TME through phagocytosis and immune activation, addressing the challenges of solid tumor infiltration. This review compares the mechanisms of action, clinical applications, and safety profiles of CAR-NK cells and CAR-macrophages, highlighting the synergistic potential of these therapies. Although clinical research on both therapies is still in its early stages, the promising preclinical and early clinical trial results underscore their potential as alternative immunotherapies for refractory cancers. Future research will focus on overcoming challenges in production scalability, improving in vivo persistence, and personalizing CAR therapies through precision medicine approaches. These two therapies will likely play pivotal roles in the next generation of cancer immunotherapies.

Specific ECM degradation potentiates the antitumor activity of CAR-T cells in solid tumors.

Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors.

Development and validation of the post-CAR prognostic index for large B-cell lymphoma patients after CAR-T progression in third or later line treatment

Chimeric antigen receptor (CAR) T-cell therapy fails to achieve durable responses in over 60% of relapsed/refractory (R/R) large B-cell lymphoma (LBCL) patients in the third or later line setting. After CAR-T failure, survival outcomes are heterogeneous and a prognostic model in this patient population is lacking. A training cohort of 216 patients with progressive disease (PD) after CAR-T from 12 Spanish centers was used to develop the Post-CAR Prognostic Index (PC-PI); primary endpoint was overall survival (OS) from CAR-T progression. Validation was performed in an external cohort from three different European centers (n = 204). The prognostic score incorporated five variables, assessed at time of PD to CAR-T: ECOG (> 0), hemoglobin (< 10 g/dL), LDH (≥ 2xULN), number of extranodal sites (> 1) and time from CAR-T to PD (< 4 months). Patients were classified in four risk groups with distinct OS (p-value < 0.05 in all comparisons). In the validation cohort, median OS in the low (31%), intermediate-low (26%), intermediate-high (17%) and high risk (26%) were 15.7, 7.1, 1.8 and 1.0 months, respectively (p < 0.05 in all comparisons). Results were consistent following adjustment for subsequent treatment. In the external cohort, the PC-PI showed a C-statistic of 0.79 (95%CI 0.76–0.82), outperforming IPI and R-IPI. In conclusion, the PC-PI score is a novel tool for OS prediction and could facilitate risk-adapted management of LBCL patients relapsing after CAR T-cells. Additionally, these results will help stratification and interpretation of trials and real-world data incorporating CART-exposed patients.

Emerging CART Therapies for Pediatric Acute Myeloid Leukemia.

The prognosis of children with acute myeloid leukemia (AML) has improved incrementally over the last decades. However, at relapse, overall survival (OS) ∼40% to 50% and is even lower for patients with chemorefractory disease. Effective and less-toxic therapies are urgently needed for these children. In the last years, immune-directed therapies such as chimeric antigen receptor (CAR)-T cells were introduced, which showed outstanding clinical activity against B-cell malignancies. CART therapies are being developed for AML on the basis of the results obtained for other hematologic malignancies. The biggest challenge of CART therapy for AML is to identify a specific target antigen, since antigens expressed in AML cells are usually shared with healthy hematopoietic stem cells. An overview of prospects of CART in pediatric AML, focused on the common antigens targeted by CART in AML that have been tested or are currently under investigation, is provided in this manuscript.

Advancements in colorectal cancer detection: The role of immuno‐positron emission tomography, immuno‐single‐photon emission computed tomography, and machine learning applications

AbstractColorectal cancer (CRC) ranks as the world's second most prevalent cancer and third in mortality. Detection and diagnosis are crucial in research and clinical settings. While colonoscopy and computed tomographic colonography are widely used for identifying organic lesions, positron emission tomography (PET) and single‐photon emission computed tomography (SPECT) offer superior visualization of molecular changes. These immuno‐PET and immuno‐SPECT techniques surpass conventional [18F] Fluorodeoxyglucose PET/CT in specificity and sensitivity, improving CRC diagnostics and supporting therapeutic strategies. This review emphasizes the role of immuno‐PET/SPECT in CRC diagnosis and establishing a foundation for therapeutic strategies, facilitating hierarchical management through the identification of treatment‐responsive populations, prediction of therapeutic outcomes, and support for intraoperative imaging. This review introduces the preclinical and clinical utility of immunoconjugates for detecting colorectal adenomas, and primary, metastatic, or recurrent CRC, focusing on specific CRC cell targets like the epidermal growth factor receptor and carcinoembryonic antigen. The review also covers various mAb‐based immunoconjugates and engineered mAb fragments, including diabodies and minibodies. Finally, it looks into the great promise of machine learning in PET or SPECT and it addresses the challenges of translating preclinical successes into clinical practice for colorectal adenoma diagnosis, proposing potential solutions and directions for future research.

Membrane Antigen Targeting in Acute Myeloid Leukemia Using Antibodies or CAR-T Cells.

This review explores the emerging area of the therapeutic use of antibodies and chimeric antigen receptor (CAR)-T cells for the treatment of acute myeloid leukemia (AML). Through a detailed analysis of the existing literature, this paper highlights the different categories of AML antigens for immunotherapeutic targeting, the most recent applications on antibodies, including bispecific immune cell engagers and CAR-T cells, to the therapy of patients with refractory/relapsing AML The studies performed in AML patients using BisAbs and CAR-T cells have shown that only a limited number of AML patients show sustained responses to these therapies, thus underlying AML heterogeneity as a major challenge. Several studies have addressed the potential mechanisms underlying the resistance of AMLs to antibody-directed immunotherapies. A better understanding of the barriers hampering the successful development of AML immunotherapy is required. However, in spite of the limitations, the studies recently carried out have shown the peculiar sensitivity of some AML subtypes to immunotherapy and have provided the basis for future studies, such as multiplex antigen targeting, which hold the promise of successful development.

GD2 in Breast Cancer: A Potential Biomarker and Therapeutic Target.

Expression of disialoganglioside GD2 in normal tissues is primarily limited to the central nervous system, peripheral sensory nerve fibers, dermal melanocytes, lymphocytes, and mesenchymal stem cells. Its widespread overexpression in various cancer types allows it to be classified as a tumor-associated antigen with potential diagnostic and therapeutic implications. This article reviews the synthesis pathways of GD2 and its role in cancer cell adhesion, proliferation, and metastasis with a focus on breast cancer. GD2 appears to be overexpressed on the outer membrane of most breast cancer cells and breast cancer stem cells (BCSCs) and is closely linked to epithelial-mesenchymal transition (EMT). GD3 synthase (GD3S) is considered to be the rate-determining step in GD2 synthesis. Clinical studies indicate that GD2 expression is increased in 35-70% of breast cancer samples, with higher levels in triple-negative breast cancer (TNBC). This overexpression correlates with more aggressive tumor features and worse prognosis. Therapeutic targeting of GD2 with monoclonal antibodies (moABs) like dinutuximab and naxitamab has demonstrated anti-cancer activity in preclinical cancer models and human clinical trials against high-risk neuroblastoma reducing tumor growth and enhancing survival. GD2-specific chimeric antigen receptor (CAR) T-cell therapy and GD3S inhibition present other promising therapeutic strategies to improve clinical outcomes. Furthermore, GD2-targeted vaccines are currently being investigated in cancer therapy. This narrative review article underscores the critical role of GD2 in breast cancer pathogenesis and highlights the promising therapeutic opportunities it offers. It advocates for the initiation of clinical trials to further explore the potential of GD2-targeted treatment in combination with standard breast cancer therapies.