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The New England Journal of Medicine Jun 2024The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an...
BACKGROUND
The risk of second tumors after chimeric antigen receptor (CAR) T-cell therapy, especially the risk of T-cell neoplasms related to viral vector integration, is an emerging concern.
METHODS
We reviewed our clinical experience with adoptive cellular CAR T-cell therapy at our institution since 2016 and ascertained the occurrence of second tumors. In one case of secondary T-cell lymphoma, a broad array of molecular, genetic, and cellular techniques were used to interrogate the tumor, the CAR T cells, and the normal hematopoietic cells in the patient.
RESULTS
A total of 724 patients who had received T-cell therapies at our center were included in the study. A lethal T-cell lymphoma was identified in a patient who had received axicabtagene ciloleucel therapy for diffuse large B-cell lymphoma, and both lymphomas were deeply profiled. Each lymphoma had molecularly distinct immunophenotypes and genomic profiles, but both were positive for Epstein-Barr virus and were associated with and mutant clonal hematopoiesis. No evidence of oncogenic retroviral integration was found with the use of multiple techniques.
CONCLUSIONS
Our results highlight the rarity of second tumors and provide a framework for defining clonal relationships and viral vector monitoring. (Funded by the National Cancer Institute and others.).
Topics: Female; Humans; Middle Aged; Biological Products; Clonal Hematopoiesis; Herpesvirus 4, Human; Immunotherapy, Adoptive; Lymphoma, Large B-Cell, Diffuse; Lymphoma, T-Cell; Neoplasms, Second Primary; Receptors, Chimeric Antigen; Antineoplastic Agents, Immunological; Virus Integration
PubMed: 38865660
DOI: 10.1056/NEJMoa2401361 -
ImmunoHorizons Jun 2024T cell activation is an essential step in chimeric Ag receptor (CAR) T (CAR T) cell manufacturing and is accomplished by the addition of activator reagents that trigger...
T cell activation is an essential step in chimeric Ag receptor (CAR) T (CAR T) cell manufacturing and is accomplished by the addition of activator reagents that trigger the TCR and provide costimulation. We explore several T cell activation reagents and examine their effects on key attributes of CAR T cell cultures, such as activation/exhaustion markers, cell expansion, gene expression, and transduction efficiency. Four distinct activators were examined, all using anti-CD3 and anti-CD28, but incorporating different mechanisms of delivery: Dynabeads (magnetic microspheres), TransAct (polymeric nanomatrix), Cloudz (alginate hydrogel), and Microbubbles (lipid membrane containing perfluorocarbon gas). Clinical-grade lentiviral vector was used to transduce cells with a bivalent CD19/CD22 CAR, and cell counts and flow cytometry were used to monitor the cells throughout the culture. We observed differences in CD4/CD8 ratio when stimulating with the Cloudz activator, where there was a significant skewing toward CD8 T cells. The naive T cell subset expressing CD62L+CCR7+CD45RA+ was the highest in all donors when stimulating with Dynabeads, whereas effector/effector memory cells were highest when using the Cloudz. Functional assays demonstrated differences in killing of target cells and proinflammatory cytokine secretion, with the highest killing from the Cloudz-stimulated cells among all donors. This study demonstrates that the means by which these stimulatory Abs are presented to T cells contribute to the activation, resulting in differing effects on CAR T cell function. These studies highlight important differences in the final product that should be considered when manufacturing CAR T cells for patients in the clinic.
Topics: Receptors, Chimeric Antigen; Humans; Lymphocyte Activation; Immunotherapy, Adoptive; CD8-Positive T-Lymphocytes; T-Lymphocytes; Phenotype; Receptors, Antigen, T-Cell; Antigens, CD19
PubMed: 38864817
DOI: 10.4049/immunohorizons.2400008 -
Cancer Medicine Jun 2024Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a...
BACKGROUND
Promising outcomes have been observed in multiple myeloma (MM) with the use of immunotherapies, specifically chimeric antigen receptor T (CAR-T) cell therapy. However, a portion of MM patients do not respond to CAR-T therapy, and the reasons for this lack of response remain unclear. The objective of this study was to investigate the impact of miR-34a on the immunosuppressive polarization of macrophages obtained from MM patients.
METHODS
The levels of miR-34a and TLR9 (Toll-like receptor 9) were examined in macrophages obtained from both healthy individuals and patients with MM. ELISA was employed to investigate the cytokine profiles of the macrophage samples. Co-culture experiments were conducted to evaluate the immunomodulatory impact of MM-associated macrophages on CAR-T cells.
RESULTS
There was an observed suppressed activation of macrophages and CD4 T lymphocytes in the blood samples of MM patients. Overexpression of miR-34a in MM-associated macrophages dampened the TLR9 expression and impaired the inflammatory polarization. In both the co-culture system and an animal model, MM-associated macrophages suppressed the activity and tumoricidal effect of CAR-T cells in a miR-34a-dependent manner.
CONCLUSION
The findings imply that targeting the macrophage miR-34a/TLR9 axis could potentially alleviate the immunosuppression associated with CAR-T therapy in MM patients.
Topics: Multiple Myeloma; MicroRNAs; Toll-Like Receptor 9; Humans; Animals; Mice; Signal Transduction; Coculture Techniques; Tumor-Associated Macrophages; Macrophages; Immunotherapy, Adoptive; Male; Female; Macrophage Activation; Cell Line, Tumor
PubMed: 38864479
DOI: 10.1002/cam4.7387 -
Cancer Medicine Jun 2024Chimeric antigen receptor T-cell (CAR-T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies.... (Review)
Review
Chimeric antigen receptor T-cell (CAR-T) therapy is becoming an effective technique for the treatment of patients with relapsed/refractory hematologic malignancies. After analyzing patients with tumor progression and sustained remission after CAR-T cell therapy, many factors were found to be associated with the efficacy of CAR-T therapy. This paper reviews the factors affecting the effect of CAR-T such as tumor characteristics, tumor microenvironment and immune function of patients, CAR-T cell structure, construction method and in vivo expansion values, lymphodepletion chemotherapy, and previous treatment, and provides a preliminary outlook on the corresponding therapeutic strategies.
Topics: Humans; Receptors, Chimeric Antigen; Immunotherapy, Adoptive; Tumor Microenvironment; T-Lymphocytes; Hematologic Neoplasms; Treatment Outcome; Receptors, Antigen, T-Cell; Animals
PubMed: 38864474
DOI: 10.1002/cam4.7375 -
Nature Reviews. Immunology Jul 2024
Topics: Humans; Receptors, Antigen, T-Cell, gamma-delta; Bone Neoplasms; Animals; Immunotherapy, Adoptive; T-Lymphocytes; Mice
PubMed: 38862639
DOI: 10.1038/s41577-024-01056-y -
Blood Advances Jun 2024
Topics: Humans; Lymphoma, Large B-Cell, Diffuse; Immunotherapy, Adoptive; Receptors, Chimeric Antigen
PubMed: 38861270
DOI: 10.1182/bloodadvances.2024012870 -
Nature Reviews. Immunology Jul 2024
Topics: Humans; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; T-Lymphocytes; Animals; Respiratory System
PubMed: 38858573
DOI: 10.1038/s41577-024-01055-z -
Frontiers in Immunology 2024Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the...
INTRODUCTION
Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematological malignancies. However, its efficacy in solid tumors is limited by the immunosuppressive tumor microenvironment that compromises CAR T cell antitumor function in clinical settings. To overcome this challenge, researchers have investigated the potential of inhibiting specific immune checkpoint receptors, including A2aR (Adenosine A2 Receptor) and Tim3 (T cell immunoglobulin and mucin domain-containing protein 3), to enhance CAR T cell function. In this study, we evaluated the impact of genetic targeting of Tim3 and A2a receptors on the antitumor function of human mesothelin-specific CAR T cells (MSLN-CAR) and
METHODS
Second-generation anti-mesothelin CAR T cells were produced using standard cellular and molecular techniques. A2aR-knockdown and/or Tim3- knockdown anti-mesothelin-CAR T cells were generated using shRNA-mediated gene silencing. The antitumor function of CAR T cells was evaluated by measuring cytokine production, proliferation, and cytotoxicity through coculture with cervical cancer cells (HeLa cell line). To evaluate antitumor efficacy of manufactured CAR T cells, tumor growth and mouse survival were monitored in a human cervical cancer xenograft model.
RESULTS
experiments demonstrated that knockdown of A2aR alone or in combination with Tim3 significantly improved CAR T cell proliferation, cytokine production, and cytotoxicity in presence of tumor cells in an antigen-specific manner. Furthermore, in the humanized xenograft model, both double knockdown CAR T cells and control CAR T cells could effectively control tumor growth. However, single knockdown CAR T cells were associated with reduced survival in mice.
CONCLUSION
These findings highlight the potential of concomitant genetic targeting of Tim3 and A2a receptors to augment the efficacy of CAR T cell therapy in solid tumors. Nevertheless, caution should be exercised in light of our observation of decreased survival in mice treated with single knockdown MSLN-CAR T cells, emphasizing the need for careful efficacy considerations.
Topics: Humans; Animals; Mesothelin; Hepatitis A Virus Cellular Receptor 2; Female; Uterine Cervical Neoplasms; Mice; Immunotherapy, Adoptive; Xenograft Model Antitumor Assays; Receptors, Chimeric Antigen; T-Lymphocytes; Cell Line, Tumor; Tumor Microenvironment; Mice, SCID
PubMed: 38855110
DOI: 10.3389/fimmu.2024.1362904 -
Frontiers in Immunology 2024Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T... (Comparative Study)
Comparative Study
INTRODUCTION
Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective.
METHODS
A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients.
RESULTS
The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively.
DISCUSSION
This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.
Topics: Humans; Lymphoma, Follicular; Cost-Benefit Analysis; United States; Biological Products; Male; Antibodies, Bispecific; Female; Immunotherapy, Adoptive; Antibodies, Monoclonal, Humanized; Middle Aged; Antineoplastic Agents, Immunological; Adult; Quality-Adjusted Life Years; Neoplasm Recurrence, Local; Aged
PubMed: 38855109
DOI: 10.3389/fimmu.2024.1393939 -
Cell Stem Cell Jun 2024Chimeric antigen receptor (CAR) macrophages have broadened the landscape of anti-cancer immunotherapies to combat solid malignancies. Shah et al. introduce CARs to...
Chimeric antigen receptor (CAR) macrophages have broadened the landscape of anti-cancer immunotherapies to combat solid malignancies. Shah et al. introduce CARs to facilitate a CAR macrophage therapy, which aims to recruit and activate T/natural killer cells, further strengthening the overall immune response to decrease pancreatic cancer burden and metastatic spreading.
Topics: Humans; Macrophages; Receptors, Chimeric Antigen; Neoplasms; Immunotherapy; Animals; Immunotherapy, Adoptive; Killer Cells, Natural; Pancreatic Neoplasms
PubMed: 38848684
DOI: 10.1016/j.stem.2024.05.006