Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells. DOI
Megen C Wittling, Hannah M. Knochelmann, Megan M. Wyatt

и другие.

Опубликована: Дек. 18, 2023

Abstract Background Mechanisms by which distinct methods of host preconditioning impact the efficacy adoptively transferred antitumor T helper cells is unknown. Methods CD4 + with a transgenic TCR that recognize TRP-1 melanoma antigen were polarized to 17 (Th17) phenotype and then into melanoma-bearing mice preconditioned either total body irradiation or chemotherapy. Results We found non-myeloablative dose (TBI 5 Gy) was more effective than using an equivalently dosed chemotherapy (CTX at 200 mg/kg) augmenting therapeutic activity anti-tumor Th17 cells. Anti-tumor engrafted better following TBI regressed large established in all animals. Conversely, only half survived long-term when CTX infused anti-melanoma IL-17 IFN-g produced cells, detected animals given preconditioning. Interestingly, inflammatory cytokines (G-CSF, IL-6, MCP-1, IL-5, KC) significantly elevated serum versus after therapy. Conclusions Our results indicate, for first time, response, persistence, cytokine profiles resulting from therapy are impacted specific regimen This work important understanding mechanisms promote long-lived responses ACT, particularly as based cell therapies now emerging clinic.

Язык: Английский

Targeting the activated microenvironment with endosialin (CD248)-directed CAR-T cells ablates perivascular cells to impair tumor growth and metastasis DOI Creative Commons
Sarah Ash, Rebecca Orha, Holly Mole

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(2), С. e008608 - e008608

Опубликована: Фев. 1, 2024

Targeting of solid cancers with chimeric antigen receptor (CAR)-T cells is limited by the lack suitable tumor-specific antigens and immunosuppressive, desmoplastic tumor microenvironment that impedes CAR-T cell infiltration, activity persistence. We hypothesized targeting endosialin (CD248) receptor, strongly expressed tumor-associated pericytes perivascular cancer-associated fibroblasts, would circumvent these challenges offer an exciting for therapy due to close proximity target vasculature, expression in normal tissues phenotype observed knockout mice. generated endosialin-directed E3K from three immunocompetent mouse strains, BALB/c, FVB/N C57BL/6. composition (CD4+/CD8+ ratio), vitro against endosialin+ endosialin- cells, expansion vivo syngeneic models as well tumor-naive healthy wounded mice tumor-bearing was assessed. were active both human endosialin+, but not endosialin-, cells. Adoptively transferred exhibited no mice, wildtype or wound healing models, demonstrating absence off-target on-target/off-tumor activity. By contrast, adoptive transfer into C57BL/6 bearing breast lung cancer lines depleted stroma resulting increased necrosis, reduced growth a substantial impairment metastatic outgrowth. Together data highlight viable stromal closely associated vasculature avoids having navigate harsh immunosuppressive microenvironment. Further, ability recognize makes humanized optimized CAR promising candidate clinical development applicable broad range types.

Язык: Английский

Процитировано

11
Recent Updates on Chimeric Antigen Receptor T-Cell Approaches in Cancer Immunotherapy DOI Creative Commons
Maryam Sahlolbei, Amirhossein Ahmadieh-Yazdi,

Mohadeseh Rostamipoor

и другие.

IntechOpen eBooks, Год журнала: 2024, Номер unknown

Опубликована: Май 15, 2024

Chimeric antigen receptor (CAR) T-cell therapy is a revolutionary development in the field of cancer immunotherapy, offering targeted approach to combat various hematologic malignancies. In this treatment, patient’s genetically modified T cells are extracted and transformed produce chimeric receptors (CARs) that exclusive cells. These altered identify, attach to, destroy when they reinfused back into patient, customized course therapy. While CAR therapy’s clinical success has been most evident cases acute lymphoblastic leukemia certain types lymphomas, ongoing research aims extend its applicability solid tumors. Despite promise, challenges like cytokine release syndrome high cost treatment remain. Nonetheless, heralds new era potentially curative for patients with otherwise refractory diseases.

Язык: Английский

Процитировано

5
ReCARving the future: bridging CAR T-cell therapy gaps with synthetic biology, engineering, and economic insights DOI Creative Commons
Alaa M. Ali, John F. DiPersio

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Сен. 5, 2024

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of hematologic malignancies, offering remarkable remission rates in otherwise refractory conditions. However, its expansion into broader oncological applications faces significant hurdles, including limited efficacy solid tumors, safety concerns related to toxicity, and logistical challenges manufacturing scalability. This review critically examines latest advancements aimed at overcoming these obstacles, highlighting innovations CAR engineering, novel targeting strategies, improvements delivery persistence within tumor microenvironment. We also discuss development allogeneic T cells as off-the-shelf therapies, strategies mitigate adverse effects, integration with other therapeutic modalities. comprehensive analysis underscores synergistic potential enhance safety, efficacy, accessibility providing a forward-looking perspective on their evolutionary trajectory cancer treatment.

Язык: Английский

Процитировано

4
DNA-Dependent Protein Kinase Inhibitors PI-103 and Samotolisib Augment CRISPR/Cas9 Knock-in Efficiency in Human T Cells DOI Creative Commons
Emina Džafo, Morteza Hafezi,

Greta Maria Paola Giordano Attianese

и другие.

Cytotherapy, Год журнала: 2025, Номер unknown

Опубликована: Фев. 1, 2025

Язык: Английский

Процитировано

0
Recent developments on checkpoint inhibitors, CAR T cells, and beyond for T cell-based immunotherapeutic strategies against cancer DOI

Shaukat Ali,

Mahnoor Arshad,

Muhammad Summer

и другие.

Journal of Oncology Pharmacy Practice, Год журнала: 2025, Номер unknown

Опубликована: Март 28, 2025

Objective There was a dire need to construct review of the recent developments on Immune checkpoint inhibitors (ICIs), CAR T Cells, and other approaches for cell-based immunotherapeutic strategies against cancer as has become one most fatal diseases that is responsible causing several deaths per annum. Data sources Multiple published data acquired from high-impact factor journal articles. summary clinical have been in use today such radiotherapy, chemotherapy immunotherapy treat different types. Among novel management strategies, role by cells immensely important. Cancer revolutionized treatment it basically utilizes body's immune system cancer. At forefront this revolution, are considered fundamental components system. Conclusions The current explores therapeutic potential fight applying various ICIs (PD-1/PD-L1, CTLA-4, TIGIT, BTLA, TIM3, LAG3) adoptive cell therapy. stimulate existing anti-tumor T-cell response way removing inhibitors. On hand, therapy (ACT) patient's modified identify attack tumor cells. Furthermore, also highlights significant successes observed with these therapies, notably PD-1 blockade tumors. Moreover, vaccination, bispecific antibodies cytokine enhance antitumor activity. Therapeutic vaccines expose tumor-associated antigens training then cells, showing promising results types cancers prostate melanoma. While, accompanied cytokines interleukin-2 (IL-2) activity proliferation, thereby boosting overall response. Lastly, future immunotherapy, envisioning advancements design gene editing techniques can efficacy across broader spectrum cancers.

Язык: Английский

Процитировано

0
In Situ Cancer Vaccines: Redefining Immune Activation in the Tumor Microenvironment DOI
Prabhanjan S. Giram, Kazi Md Mahabubur Rahman,

Osama Aqel

и другие.

ACS Biomaterials Science & Engineering, Год журнала: 2025, Номер unknown

Опубликована: Апрель 14, 2025

Cancer is one of the leading causes mortality worldwide. Nanomedicines have significantly improved life expectancy and survival rates for cancer patients in current standard care. However, recurrence due to metastasis remains a significant challenge. Vaccines can provide long-term protection are ideal preventing bacterial viral infections. vaccines, however, shown limited therapeutic efficacy raised safety concerns despite extensive research. vaccines target stimulate responses against tumor-specific antigens demonstrated great potential treatment preclinical studies. tumor-associated immunosuppression immune tolerance driven by immunoediting pose challenges vaccine design. In situ vaccination represents an alternative approach traditional vaccines. This strategy involves intratumoral administration immunostimulants modulate growth differentiation innate cells, such as dendritic macrophages, neutrophils, restore T-cell activity. Currently approved T-VEC, clinical promise, while ongoing trials continue explore novel strategies broader efficacy. Despite these advancements, failures research highlight need address suppression escape mechanisms. combine adaptive stimulation, leveraging activate cells cross-prime CD8+ T cells. Various modalities, nucleotide-based (e.g., RNA DNA vaccines), peptide-based cell-based (including dendritic, T-cell, B-cell approaches), show potential. Plant-based approaches, including cowpea mosaic virus Newcastle disease virus, further expand toolkit vaccination. Therapeutic modalities chemotherapy, radiation, photodynamic therapy, photothermal Checkpoint blockade inhibitors contribute enhanced antigen presentation activation. Adjuvants like CpG-ODN PRR agonists enhance modulation The advantages include patient specificity, personalization, minimized escape, reduced logistical costs. barriers tumor heterogeneity, evasion, remain. review explores developing potent examines trials, evaluates stimulation methods, discusses prospects advancing

Язык: Английский

Процитировано

0
Combining SiRPα decoy–coengineered T cells and antibodies augments macrophage-mediated phagocytosis of tumor cells DOI Creative Commons
Evangelos Stefanidis, Aikaterini Semilietof,

J. Olmedo Pujol

и другие.

Journal of Clinical Investigation, Год журнала: 2024, Номер 134(11)

Опубликована: Апрель 23, 2024

The adoptive transfer of T cell receptor-engineered (TCR-engineered) cells (ACT) targeting the HLA-A2-restricted cancer-testis epitope NY-ESO-1157-165 (A2/NY) has yielded favorable clinical responses against several cancers. Two approaches to improve ACT are TCR affinity optimization and coengineering express immunomodulatory molecules that can exploit endogenous immunity. By computational design we previously developed a panel binding-enhanced A2/NY-TCRs including A97L, which augmented in vitro function gene-modified as compared with WT. Here, demonstrated higher persistence improved tumor control by A97L-T cells. In order harness macrophages tumors, further coengineered secrete high-affinity signal regulatory protein α (SiRPα) decoy (CV1) blocks CD47. While CV1-Fc-coengineered mediated significantly better outgrowth survival Winn assays, subcutaneous xenograft models cells, coated CV1-Fc, were depleted. Importantly, there was no phagocytosis CV1 monomer-coengineered human macrophages. Moreover, avelumab cetuximab enhanced macrophage-mediated presence upon coadministration Taken together, our study indicates important promise for harnessing combining CV1-coengineered TCR-T targeted antibodies direct

Язык: Английский

Процитировано

3
TALEN-edited Allogeneic Inducible Dual CAR T-cells Enable Effective Targeting of Solid Tumors while Mitigating Off-Tumor Toxicity DOI Creative Commons

Sonal Dharani,

Hana Cho, Jorge Postigo

и другие.

Molecular Therapy, Год журнала: 2024, Номер 32(11), С. 3915 - 3931

Опубликована: Авг. 23, 2024

Adoptive cell therapy using chimeric antigen receptor (CAR) T cells has proven to be lifesaving for many cancer patients. However, its therapeutic efficacy been limited in solid tumors. One key factor this is cancer-associated fibroblasts (CAFs) that modulate the tumor microenvironment (TME) inhibit infiltration and induce "T dysfunction." Additionally, sparsity of tumor-specific antigens (TSA) expression CAR-directed tumor-associated (TAA) on normal tissues often results "on-target off-tumor" cytotoxicity, raising safety concerns. Using TALEN-mediated gene editing, we present here an innovative CAR engineering strategy overcome these challenges. Our allogeneic "Smart cells" are designed express a constitutive CAR, targeting FAP+ CAFs second TAA such as mesothelin specifically integrated at TCR signaling-inducible locus like PDCD1. FAPCAR-mediated CAF induces establishing IF/THEN-gated circuit sensitive dual sensing. approach, observe enhanced anti-tumor while limiting toxicity. study thus demonstrates editing capabilities design efficiently target immunotherapy-recalcitrant tumors mitigating potential risks, encouraging clinical development strategy.Graphical abstract

Язык: Английский

Процитировано

3
Distinct host preconditioning regimens differentially impact the antitumor potency of adoptively transferred Th17 cells DOI Creative Commons
Megen C Wittling, Hannah M. Knochelmann,

Megan M Wyatt

и другие.

Journal for ImmunoTherapy of Cancer, Год журнала: 2024, Номер 12(6), С. e008715 - e008715

Опубликована: Июнь 1, 2024

Background How distinct methods of host preconditioning impact the efficacy adoptively transferred antitumor T helper cells is unknown. Methods CD4 + with a transgenic T-cell receptor that recognize tyrosinase-related peptide (TRP)-1 melanoma antigen were polarized to 17 (Th17) phenotype and then into melanoma-bearing mice preconditioned either total body irradiation or chemotherapy. Results We found non-myeloablative dose (TBI 5 Gy) was more effective than using an equivalently dosed chemotherapy (cyclophosphamide (CTX) 200 mg/kg) at augmenting therapeutic activity TRP-1 Th17 cells. Antitumor engrafted better following TBI regressed large established in all animals. Conversely, only half survived long-term when CTX infused anti-melanoma Interleukin (IL)-17 interferon-γ, produced by cells, detected animals given preconditioning. Interestingly, inflammatory cytokines (granulocyte colony stimulating factor, IL-6, monocyte chemoattractant protein-1, IL-5, keratinocyte chemoattractant) significantly elevated serum versus after therapy. The addition fludarabine (FLU, (200 improved response same degree mediated TBI, whereas FLU alone therapy ineffective. Conclusions Our results indicate, for first time, response, persistence, cytokine profiles resulting from are impacted specific regimen This work important understanding mechanisms promote long-lived responses adoptive cellular therapy, particularly as based therapies now emerging clinic.

Язык: Английский

Процитировано

2
Metabolic predictors of response to immune checkpoint blockade therapy DOI Creative Commons
Ofir Shorer, Keren Yizhak

iScience, Год журнала: 2023, Номер 26(11), С. 108188 - 108188

Опубликована: Окт. 12, 2023

Metabolism of immune cells in the tumor microenvironment (TME) plays a critical role cancer patient response to checkpoint inhibitors (ICI). Yet, metabolic characterization TME patients treated with ICI is lacking. To bridge this gap we performed semi-supervised analysis ∼1700 genes using single-cell RNA-seq data > 1 million from ∼230 samples ICI. When clustering based on their gene expression, found that similar immunological cellular states are different states. Most importantly, significantly associated response. We then built predictor dozen signature, which differentiates between responding and non-responding across types (AUC = 0.8-0.92). Taken together, our results demonstrate power metabolism predicting

Язык: Английский

Процитировано

4