Tetraspanins in digestive­system cancers: Expression, function and therapeutic potential (Review).

The tetraspanin family of membrane proteins is essential for controlling different biological processes such as cell migration, penetration, adhesion, growth, apoptosis, angiogenesis and metastasis. The present review summarized the current knowledge regarding the expression and roles of tetraspanins in different types of cancer of the digestive system, including gastric, liver, colorectal, pancreatic, esophageal and oral cancer. Depending on the type and context of cancer, tetraspanins can act as either tumor promoters or suppressors. In the present review, the importance of tetraspanins in serving as biomarkers and targets for different types of digestive system­related cancer was emphasized. Additionally, the molecular mechanisms underlying the involvement of tetraspanins in cancer progression and metastasis were explored. Furthermore, the current challenges are addressed and future research directions for advancing investigations related to tetraspanins in the context of digestive system malignancies are proposed.

Several factors that predict the outcome of large B-cell lymphoma patients who relapse/progress after chimeric antigen receptor (CAR) T-cell therapy can be identified before cell administration.

AIM: The aim of this study was to analyse the outcomes of patients with large B-cell lymphoma (LBCL) treated with chimeric antigen receptor T-cell therapy (CAR-Tx), with a focus on outcomes after CAR T-cell failure, and to define the risk factors for rapid progression and further treatment. METHODS: We analysed 107 patients with LBCL from the Czech Republic and Slovakia who were treated in ≥3rd-line with tisagenlecleucel or axicabtagene ciloleucel between 2019 and 2022. RESULTS: The overall response rate (ORR) was 60%, with a 50% complete response (CR) rate. The median progression-free survival (PFS) and overall survival (OS) were 4.3 and 26.4 months, respectively. Sixty-three patients (59%) were refractory or relapsed after CAR-Tx. Of these patients, 39 received radiotherapy or systemic therapy, with an ORR of 22% (CR 8%). The median follow-up of surviving patients in whom treatment failed was 10.6 months. Several factors predicting further treatment administration and outcomes were present even before CAR-Tx. Risk factors for not receiving further therapy after CAR-Tx failure were high lactate dehydrogenase (LDH) levels before apheresis, extranodal involvement (EN), high ferritin levels before lymphodepletion (LD) and ECOG PS >1 at R/P. The median OS-2 (from R/P after CAR-Tx) was 6.7 months (6-month 57.9%) for treated patients and 0.4 months (6-month 4.2%) for untreated patients (p < 0.001). The median PFS-2 (from R/P after CAR-Tx) was 3.2 months (6-month 28.5%) for treated patients. The risk factors for a shorter PFS-2 (n = 39) included: CRP > limit of the normal range (LNR) before LD, albumin < LNR and ECOG PS > 1 at R/P. All these factors, together with LDH > LNR before LD and EN involvement at R/P, predicted OS-2 for treated patients. CONCLUSION: Our findings allow better stratification of CAR-Tx candidates and stress the need for a proactive approach (earlier restaging, intervention after partial remission achievement).

Recent updates on allogeneic CAR-T cells in hematological malignancies.

CAR-T cell therapy is known as an effective therapy in patients with hematological malignancies. Since 2017, several autologous CAR-T cell (auto-CAR-T) drugs have been approved by the US Food and Drug Administration (FDA) for the treatment of some kinds of relapsed/refractory hematological malignancies. However, some patients fail to respond to these drugs due to high manufacturing time, batch-to-batch variation, poor quality and insufficient quantity of primary T cells, and their insufficient expansion and function. CAR-T cells prepared from allogeneic sources (allo-CAR-Ts) can be an alternative option to overcome these obstacles. Recently, several allo-CAR-Ts have entered into the early clinical trials. Despite their promising preclinical and clinical results, there are two main barriers, including graft-versus-host disease (GvHD) and allo-rejection that may decline the safety and efficacy of allo-CAR-Ts in the clinic. The successful development of these products depends on the starter cell source, the gene editing method, and the ability to escape immune rejection and prevent GvHD. Here, we summarize the gene editing technologies and the potential of various cell sources for developing allo-CAR-Ts and highlight their advantages for the treatment of hematological malignancies. We also describe preclinical and clinical data focusing on allo-CAR-T therapy in blood malignancies and discuss challenges and future perspectives of allo-CAR-Ts for therapeutic applications.

Prevalence of non-Hodgkin lymphoma patients at high-risk of failure after CAR T-cell therapy eligible for bridging radiation therapy.

Background and purpose: The aim of this study was to determine the prevalence of patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) meeting high-risk criteria for early relapse after CD19 CAR T-cell therapy (CART) who have disease encompassable in a standard radiation therapy (RT) plan (defined as <5 malignant lesions) and may benefit from bridging RT prior to CD19 CART. Materials and methods: This is a single-center, retrospective study of patients with R/R NHL who received CD19 CART from 2018 to 2022. Eligible patients had pre-apheresis radiologic studies available. All patients were classified by number of lesions and history of high-risk disease criteria: bulky disease ≥10 cm, ≥1 extranodal (EN) sites, LDH ≥normal, or ≥1 lesion with SUVmax ≥10. Results: A total of 81 patients with R/R NHL were evaluated. Based on our definition, 40 (49%) patients would have been eligible for bridging RT, including 38 patients who met high-risk criteria: 31 with ≥1 EN site, 19 had ≥1 lesion with SUVmax ≥10, 16 with bulky disease, and 3 with elevated LDH. At 3 months after CART, ORRs in high-risk patients with <5 lesions, ≥5 lesions, and no lesions on pre-apheresis studies were 76% (CR 69%, PR 7%), 70% (CR 60%, PR 10%), and 80% (CR 80%), respectively. Conclusion: Approximately 47% (38/81) of patients were classified as at high risk of relapse after CART with disease encompassable in a standard radiation plan and eligible for bridging RT studies.

Patterns of metabolic response in patients receiving commercial CAR T-cells for relapsing/refractory aggressive B cells lymphoma.

CAR T-cells is an innovative treatment for relapsed/refractory aggressive B cell lymphomas, initially proposed as third line therapy and beyond, now allowed as soon as second-line treatment for patients with early relapse after first-line treatment. FDG PET/CT remains the modality of choice to evaluate response to this therapeutic strategy, to detect or confirm treatment failure and allow for salvage therapy if needed. Correct classification of patients regarding response is thus of the utmost importance. In many cases, metabolic response follows classical known patterns, and Deauville score and Lugano criteria yield accurate characterization of patient status. However, given its specific mode of action, it can result in delayed response or atypical patterns of response. We report here a few examples of response from our experience to illustrate the existence of tricky cases. These atypical cases require multidisciplinary management, with clinical, biological, imaging and pathological work-up.

[Clinical and transversal competencies of advanced practice nurses (APNs) within a cellular therapy team (SFGM-TC)]. / Compétences cliniques et transversales des infirmier(e)s en pratique avancée (IPA) au sein d'une équipe de thérapie cellulaire (SFGM-TC).

The advanced practice nurse (APN) has been introduced in France, following the 2016 health law and implementing decrees published in 2018. In this context, the French Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) has already issued guidelines regarding the allocation of APNs' new clinical competences and their collaboration with physicians. It is now providing new recommendations on the transversal activities that can be fulfilled by APNs, such as research, leadership, training and teaching. Additionally, the guidelines outline how APNs can cooperate with other professionals in departments of haematology and cellular therapy, including nurses, coordinators and health managers.

Astragalus polysaccharide enhances antitumoral effects of chimeric antigen receptor- engineered (CAR) T cells by increasing CD122+CXCR3+PD-1- memory T cells.

Chimeric antigen receptor-engineered T (CAR-T) cell therapy of cancer has been a hotspot and promising. However, due to rapid exhaustion, CAR-T cells are less effective in solid tumors than in hematological ones. CD122+CXCR3+ memory T cells are characterized with longevity, self-renewal and great antitumoral capacity. Thus, it's compelling to induce memory CAR-T cells to enhance their efficacy on solid tumors. Astragalus polysaccharide (APS) has reportedly exhibited antitumoral effects. However, it's unclear if APS has an impact on CD8+ memory T cell generation or persistence. Using two human cancer cell lines, here we found that APS significantly improved the persistence of GPC3-targeted CAR-T cells and enhanced their suppression of tumor growth in both Huh7 and HepG2 xenograft models of hepatocellular carcinoma. APS increased CD122+/CXCR3+ memory T cells, but decreased their PD-1+ subset within CD8+ CAR-T cells in tumor-bearing mice, while these effects of APS were also confirmed with in vitro experiments. Moreover, APS augmented the expression of chemokines CXCL9/CXCL10 by the tumor in vivo and in vitro. It also enhanced the proliferation and chemotaxis/migration of CAR-T cells in vitro. Finally, APS promoted the phosphorylation of STAT5 in CD8+ CAR-T cells, whereas inhibition of STAT5 activation reversed these in vitro effects of APS. Therefore, APS enhanced the antitumoral effects of CD8+ CAR-T cells by promoting formation/persistence of CD122+/CXCR3+/PD-1- memory T cells and their migration to the tumor.

Optimization of anti-TIM3 chimeric antigen receptor with CD8α spacer and TNFR-based costimulation for enhanced efficacy in AML therapy.

CAR T cell therapy for AML remains limited due to the lack of a proper target without on-target off-tumor toxicity. TIM3 is a promising target due to its high expression on AML cells and absence in most normal hematopoietic cells. Previous reports have shown that each CAR component impacts CAR functionality. Here, we optimized TIM-3 targeting CAR T cells for AML therapy. We generated CARs targeting TIM3 with two different non-signaling domains: an IgG2-CH3 spacer with CD28 transmembrane domain (CH3/CD28) and a CD8α spacer with CD8α transmembrane domain (CD8/CD8), and evaluated their characteristics and function. Incorporating the non-signaling CH3/CD28 domain resulted in unstable CAR expression in anti-TIM3 CAR T cells, leading to lower surface CAR expression over time and reduced cytotoxic function compared to anti-TIM3 CARs with the CD8/CD8 domain. Both types of anti-TIM3 CAR T cells transiently exhibited fratricide, which subsided overtime, and both CAR T cells achieved substantial T cell expansion. To further optimize the design, we explored the effects of different costimulatory domains. Compared with CD28 costimulation, 4-1BB and CD27 combined with a CD8/CD8 non-signaling domain showed higher cytokine secretion, superior antitumor activity, and enhanced T-cell persistence after repeated antigen exposure. These findings emphasize the impact of the optimal design of CAR constructs that provide efficient function. In the context of anti-TIM3 CAR T cells, using a CD8α spacer and transmembrane domain with TNFR-based costimulation is a promising CAR design to improve anti-TIM3 CAR T cell function for AML therapy.

CAR-T therapy pulmonary adverse event profile: a pharmacovigilance study based on FAERS database (2017-2023).

Background: Chimeric antigen receptor T-cell (CAR-T) therapy, a rapidly emerging treatment for cancer that has gained momentum since its approval by the FDA in 2017, involves the genetic engineering of patients' T cells to target tumors. Although significant therapeutic benefits have been observed, life-threatening adverse pulmonary events have been reported. Methods: Using SAS 9.4 with MedDRA 26.1, we retrospectively analyzed data from the Food and Drug Administration's Adverse Event Reporting System (FAERS) database, covering the period from 2017 to 2023. The analysis included the Reporting Odds Ratio Proportional Reporting Ratio Information Component and Empirical Bayes Geometric Mean to assess the association between CAR-T cell therapy and adverse pulmonary events (PAEs). Results: The FAERS database recorded 9,400 adverse events (AEs) pertaining to CAR-T therapies, of which 940 (10%) were PAEs. Among these CAR-T cell-related AEs, hypoxia was the most frequently reported (344 cases), followed by respiratory failure (127 cases). Notably, different CAR-T cell treatments demonstrated varying degrees of association with PAEs. Specifically, Tisa-cel was associated with severe events including respiratory failure and hypoxia, whereas Axi-cel was strongly correlated with both hypoxia and tachypnea. Additionally, other CAR-T therapies, namely, Brexu-cel, Liso-cel, Ide-cel, and Cilta-cel, have also been linked to distinct PAEs. Notably, the majority of these PAEs occurred within the first 30 days post-treatment. The fatality rates varied among the different CAR-T therapies, with Tisa-cel exhibiting the highest fatality rate (43.6%), followed by Ide-cel (18.8%). Conclusion: This study comprehensively analyzed the PAEs reported in the FAERS database among recipients of CAR-T cell therapy, revealing conditions such as hypoxia, respiratory failure, pleural effusion, and atelectasis. These CAR-T cell therapy-associated events are clinically significant and merit the attention of clinicians and researchers.

Cost-per-responder analysis of patients with lenalidomide-refractory multiple myeloma receiving ciltacabtagene autoleucel in CARTITUDE-4.

Introduction: Ciltacabtagene autoleucel (cilta-cel) is a chimeric antigen receptor T-cell therapy approved for patients with relapsed/refractory multiple myeloma (RRMM). In the phase 3 trial, CARTITUDE-4 (NCT04181827), cilta-cel demonstrated improved efficacy vs. standard of care (SOC; daratumumab plus pomalidomide and dexamethasone [DPd] or pomalidomide plus bortezomib and dexamethasone [PVd]) with a ≥ complete response (≥CR) rate of 73.1% vs. 21.8%. Methods: A cost-per-responder model was developed to assess the value of cilta-cel and SOC (87% DPd and 13% PVd) based on the CARTITUDE-4 trial data from a US mixed payer perspective (76.7% commercial, 23.3% Medicare). The model was developed using progression-free survival (PFS), overall survival (OS), and ≥CR endpoints from CARTITUDE-4 over a period of 25.4 months. Inpatient stays, outpatient visits, drug acquisition, administration, and monitoring costs were included. The base-case model assumed an inpatient setting for each cilta-cel infusion; another scenario included 30% outpatient and 70% inpatient infusions. Costs of managing grade 3-4 adverse events (AEs) and grade 1-4 cytokine release syndrome and neurotoxicity were included. Subsequent therapy costs were incurred after disease progression; terminal care costs were considered upon death events. Outcomes included total cost per treated patient, total cost per complete responder, and cost per month in PFS between cilta-cel and SOC. Costs were adjusted to 2024 US dollars. Results: Total cost per treated patient, total cost per complete responder, and total cost per month in PFS were estimated at $704,641, $963,941, and $30,978 for cilta-cel, respectively, and $840,730, $3,856,559, and $42,520 for SOC over the 25.4-month period. Cost drivers included treatment acquisition costs before progression and subsequent treatment costs ($451,318 and $111,637 for cilta-cel; $529,795 and $265,167 for SOC). A scenario analysis in which 30% of patients received an outpatient infusion (assuming the same payer mix) showed a lower cost per complete responder for cilta-cel ($956,523) than those with an infusion in the inpatient setting exclusively. Discussion: This analysis estimated that cost per treated patient, cost per complete responder, and cost per month in PFS for cilta-cel were remarkably lower than for DPd or PVd, highlighting the substantial clinical and economic benefit of cilta-cel for patients with RRMM.

Potential of gamma/delta T cells for solid tumor immunotherapy.

Gamma/delta T (γδ T)cells possess a unique mechanism for killing tumors, making them highly promising and distinguished among various cell therapies for tumor treatment. This review focuses on the major histocompatibility complex (MHC)-independent recognition of antigens and the interaction between γδ T cells and solid tumor cells. A comprehensive review is provided regarding the classification of human gamma-delta T cell subtypes, the characteristics and mechanisms underlying their functions, as well as their r545egulatory effects on tumor cells. The involvement of γδ T cells in tumorigenesis and migration was also investigated, encompassing potential therapeutic targets such as apoptosis-related molecules, the TNF receptor superfamily member 6(FAS)/FAS Ligand (FASL) pathways, butyrophilin 3A-butyrophilin 2A1 (BTN3A-BTN2A1) complexes, and interactions with CD4, CD8, and natural killer (NK) cells. Additionally, immune checkpoint inhibitors such as programmed cell death protein 1/Programmed cell death 1 ligand 1 (PD-1/PD-L1) have the potential to augment the cytotoxicity of γδ T cells. Moreover, a review on gamma-delta T cell therapy products and their corresponding clinical trials reveals that chimeric antigen receptor (CAR) gamma-delta T therapy holds promise as an approach with encouraging preclinical outcomes. However, practical issues pertaining to manufacturing and clinical aspects need resolution, and further research is required to investigate the long-term clinical side effects of CAR T cells. In conclusion, more comprehensive studies are necessary to establish standardized treatment protocols aimed at enhancing the quality of life and survival rates among tumor patients utilizing γδ T cell immunotherapy.

Drug development in LMICs: could the emerging Indian model usher the southeast Asian region?

Low-income and middle-income countries (LMICs) of southeast Asia are passing through a similar phase as India in their tryst with the development of novel drugs. They are beginning to break away from their dependency on the institutions of our developed world. Over the past few years, Tata Memorial Centre-India's premier cancer centre-has shown the tenacity to develop drugs within the national frontiers. By collaborating with the domestic pharmaceutical industries, it has been able to have a steady pipeline of drugs under development, with two of them receiving marketing authorization recently. Lately, Indonesia and Vietnam have also shown an inclination towards public-private partnerships for similar motives. However, due to prolonged innovative stagnation, the entire drug development machinery faces challenges stretching all the way from arranging funds to persuading regulatory bodies. In this Viewpoint, we have tried to address a few of those issues and their potential solutions, with the intention to share our own experience which might be useful to other LMICs in connecting some adamant dots.

Locoregional CAR T Cells for the Treatment of CNS Tumors in Children: Investigational Drug Service Pharmacy Activities.

BACKGROUND: A major obstacle in translating the therapeutic potential of chimeric antigen receptor (CAR) T cells to children with central nervous system (CNS) tumors is the blood-brain barrier. To overcome this limitation, preclinical and clinical studies have supported the use of repeated, locoregional intracranial CAR T-cell delivery. However, there is limited literature available describing the process for the involvement of an investigational drug service (IDS) pharmacy, particularly in the setting of a children's hospital with outpatient dosing for CNS tumors. OBJECTIVES: To describe Seattle Children's Hospital's experience in clinically producing CAR T cells and the implementation of IDS pharmacy practices used to deliver more than 300 intracranial CAR T-cell doses to children, as well as to share how we refined the processing techniques from CAR T-cell generation to the thawing of fractionated doses for intracranial delivery. METHODS: Autologous CD4+ and CD8+ T cells were collected and transduced to express HER2, EGFR, or B7-H3-specific CAR T cells. Cryopreserved CAR T cells were thawed by the IDS pharmacy before intracranial delivery to patients with recurrent/refractory CNS tumors or with diffuse intrinsic pontine glioma/diffuse midline glioma. RESULTS: The use of a thaw-and-dilute procedure for cryopreserved individual CAR T-cell doses provides reliable viability and is more efficient than typical thaw-and-wash protocols. Cell viability with the thaw-and-dilute protocol was approximately 75% and was always within 10% of the viability assessed at cryopreservation. Cell viability was preserved through 6 hours after thawing, which exceeded the 1-hour time frame from thawing to infusion. CONCLUSION: As the field of adoptive immunotherapy grows and continues to bring hope to patients with fatal CNS malignancies, it is critical to focus on improving the preparatory steps for CAR T-cell delivery.

Novel targets and improved immunotherapeutic techniques with an emphasis on antimycosal drug resistance for the treatment and management of mycosis.

Infections due to pathogenic fungi are endemic in particular area with increased morbidity and mortality. More than a thousand people are infected per year and the way of treatment is of high demand having a significant impact on the population health. Medical practitioners confront various troublesome analytic and therapeutical challenges in the administration of immunosuppressed sufferer at high danger of expanding fungal infections. An upgraded antimycosal treatment is fundamental for a fruitful result while treating intrusive mycoses. A collection of antimycosal drugs keeps on developing with their specific antifungal targets including cell membrane, mitochondria, cell wall, and deoxyribonucleic acid (DNA)/ribonucleic acid (RNA) or protein biosynthesis. Some fundamental classes of ordinarily directed medications are the polyenes, amphotericin B, syringomycin, allylamines, honokiol, azoles, flucytosine, echinocandins etc. However, few immunotherapy processes and vaccinations are being developed to mark this need, although one presently can't seem to arrive at the conclusion. In this review article, there has been a trial to give details upgradation about the current immune therapeutic techniques and vaccination strategies against prevention or treatment of mycosis as well as the difficulties related with their turn of events. There has been also a visualization in the mentioned review paper about the various assorted drugs and their specific target analysis along with therapeutic interventions.

Targeting chronic lymphocytic leukemia with B-cell activating factor receptor CAR T cells.

The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T-cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T-cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B-cell activating factor receptor (BAFF-R) as a promising target for CAR design against CLL. BAFF-R is essential for B-cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF-R CAR T-cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19-knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF-R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient-derived CAR T cells against autologous tumor cells. Given these promising results, BAFF-R CAR T-cell therapy has the potential to meet the long-standing need for an effective treatment on CLL patients.

Engineered T cells for Colorectal Cancer.

Colorectal cancer (CRC) is a major contributor to global cancer incidence and mortality. Conventional treatments have limitations; hence, innovative approaches are imperative. Recent advancements in cancer research have led to the development of personalized targeted therapies and immunotherapies. Immunotherapy, in particular, T cell-based therapies, exhibited to be promising in enhancing cancer treatment outcomes. This review focuses on the landscape of engineered T cells as a potential option for the treatment of CRC. It highlights the approaches, challenges and current advancements in this field. As the understanding of molecular mechanisms increases, engineered T cells hold great potential in revolutionizing cancer treatment. To fully explore their safety efficacy in improving patient outcomes, further research and clinical trials are necessary.

Colorectal cancer (CRC) is a significant cause of cancer cases and cancer-related deaths globally. Current treatments for CRC have limitations; hence, there is a need for new and innovative approaches. Recent progress in cancer research has led to the development of personalized targeted therapies and immunotherapies, that is, treatments that use the body's immune system to fight cancer. T cell-based therapy is a type of immunotherapy that has shown promising outcomes in cancer treatment. This therapy involves modifying a type of immune cell called T cells to specifically target cancer cells. In this review, the focus is on the landscape of engineered T cells as a potential option for the treatment of CRC, as well as their challenges and current advancements. Generally, additional research and clinical trials are needed to fully explore its safety and efficacy in improving patient outcomes.

Looking ahead to targeting macrophages by CAR T- or NK-cells in blood cancers.

INTRODUCTION: The bone marrow microenvironment (BME) is critical for healthy hematopoiesis and is often disrupted in hematologic malignancies. Tumor-associated macrophages (TAMs) are a major cell type in the tumor microenvironment (TME) and play a significant role in tumor growth and progression. Targeting TAMs and modulating their polarization is a promising strategy for cancer therapy. AREAS COVERED: In this review, we discuss the importance of TME and different multiple possible targets to modulate immunosuppressive TAMs such as: CD123, Sphingosine 1-Phosphate Receptors, CD19/CD1d, CCR4/CCL22, CSF1R (CD115), CD24, CD40, B7 family proteins, MARCO, CD47, CD163, CD204, CD206 and folate receptors. EXPERT OPINION: Innovative approaches to combat the immunosuppressive milieu of the tumor microenvironment in hematologic malignancies are of high clinical significance and may lead to increased survival, improved quality of life, and decreased toxicity of cancer therapies. Standard procedures will likely involve a combination of CAR T/NK-cell therapies with other treatments, leading to more comprehensive cancer care.

Revolutionizing Immunotherapy: Unveiling New Horizons, Confronting Challenges, and Navigating Therapeutic Frontiers in CAR-T Cell-Based Gene Therapies.

The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.

Smoldering oncolysis by foamy virus carrying CD19 as a CAR target escapes CAR T detection by genomic modification.

Chimeric antigen receptor (CAR) T cells have had limited success against solid tumors. Here, we used an oncolytic foamy virus (oFV) to display a model CAR target antigen (CD19) on tumors in combination with anti-CD19 CAR T cells. We generated oFV-Δbel2 and oFV-bel2 vectors to test the efficiency and stability of viral/CD19 spread. While both viruses conferred equal CAR T killing in vitro, the oFV-Δbel2 virus acquired G-to-A mutations, whereas oFV-bel2 virus had genome deletions. In subcutaneous tumor models in vivo, CAR T cells led to a significant decrease in oFV-specific bioluminescence, confirming clearance of oFV-infected tumor cells. However, the most effective therapy was with high-dose oFV in the absence of CAR T cells, indicating that CAR T clearance of oFV was detrimental. Moreover, in tumors that escaped CAR T cell treatment, resurgent virus contained deletions within the oFV-CD19 transgene, allowing the virus to escape CAR T elimination. Therefore, oFV represents a slow smoldering type of oncolytic virus, whose chronic spread through tumors generates anti-tumor therapy, which is abolished by CAR T therapy. These results suggest that further development of this oncolytic platform, with additional immunotherapeutic arming, may allow for an effective combination of chronic oncolysis.