Impact of scFv on Functionality and Safety of Third-Generation CD123 CAR T Cells.

Chimeric antigen receptor (CAR) T cells express an extracellular domain consisting of a single-chain fragment variable (scFv) targeting a surface tumor-associated antigen. scFv selection should involve safety profiling with evaluation of the efficacy/toxicity balance, especially when the target antigen also is expressed on healthy cells. Here, to assess differences in terms of efficacy and on-target/off-tumor effects, we generated five different CARs targeting CD123 by substituting only the scFv.

CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy.

While CAR-T and tgTCR-T therapies have exhibited noteworthy and promising outcomes in hematologic and solid tumors respectively, a set of distinct challenges remains. Consequently, the quest for novel strategies has become imperative to safeguard and more effectively release the full functions of engineered T cells. These factors are intricately linked to the success of adoptive cell therapy.

Characterization of atypical T cells generated during expansion process for T cell-based adoptive immunotherapy.

Engineered T cell-based adoptive immunotherapies met promising success for the treatment of hematological malignancies. Nevertheless, major hurdles remain to be overcome regarding the management of relapses and the translation to solid tumor settings. Properties of T cell-based final product should be appropriately controlled to fine-tune the analysis of clinical trial results, to draw relevant conclusions, and finally to improve the efficacy of these immunotherapies.

Umbilical Cord Blood as a Source of Less Differentiated T Cells to Produce CD123 CAR-T Cells.

Chimeric Antigen Receptor (CAR) therapy has led to great successes in patients with leukemia and lymphoma. Umbilical Cord Blood (UCB), stored in UCB banks, is an attractive source of T cells for CAR-T production. We used a third generation CD123 CAR-T (CD28/4-1BB), which was previously developed using an adult's Peripheral Blood (PB), to test the ability of obtaining CD123 CAR-T from fresh or cryopreserved UCB.

Harnessing Antitumor CD4 T Cells for Cancer Immunotherapy.

Over the past decades, CD4 T cells have been considered as a supporting actor in the fields of cancer immunotherapy. Until recently, accumulating evidence has demonstrated the critical role of CD4 T cells during antitumor immunity. CD4 T cells can either suppress or promote the antitumor cytotoxic CD8 T cell responses, either in secondary lymphoid organs or in the tumor.

Homeostatic cytokines tune naivety and stemness of cord blood-derived transgenic T cells.

Engineered T-cell therapies have proven to be successful in cancer and their clinical effectiveness is directly correlated with the infused T-cell differentiation profile. Indeed, stem cell memory and central memory T cells proliferate and persist longer in vivo compared with more-differentiated T cells, while conferring enhanced antitumor activity. Here, we propose an optimized process using cord blood (CB) to generate minimally differentiated T-cell products in terms of phenotype, function, gene expression, and metabolism, using peripheral blood (PB)-derived T cells cultured with IL-2 as a standard.

Naturally Occurring Telomerase-Specific CD4 T-Cell Immunity in Melanoma.

CD4 T cells play a key role in anticancer immunity. In this study, we investigate the clinical relevance of circulating CD4 T helper type 1 (Th1) response against telomerase (anti-TERT Th1 response) in patients with melanoma. The spontaneous anti-TERT Th1 response was detected in 54.

An unmet need: Harmonization of IL-7 and IL-15 combination for the ex vivo generation of minimally differentiated T cells.

T cell-based adoptive cell transfer therapy is now clinically used to fight cancer with CD19-targeting chimeric antigen receptor T cells. The use of other T cell-based immunotherapies relying on antigen-specific T cells, genetically modified or not, is expanding in various neoplastic diseases. T cell manufacturing has evolved through sophisticated processes to produce T cells with improved therapeutic potential.

Validation of a method evaluating T cell metabolic potential in compliance with ICH Q2 (R1).

Background: Metabolic cell features are able to give reliable information on cell functional state. Thus, metabolic potential assessment of T cells in malignancy setting represents a promising area, especially in adoptive cell therapy procedures. Easy to set up and convenient Seahorse technology have recently been proposed by Agilent Technologies and it could be used to monitor T cells metabolic potential.

Investigation of the prognostic value of CD4 T cell subsets expanded from tumor-infiltrating lymphocytes of colorectal cancer liver metastases.

Background: The positive role of CD8+ tumor-infiltrating lymphocytes (TIL) in patients with colorectal cancer (CRC) has been well described but the prognostic value of CD4 T cell subsets remained to be investigated. In this study, we expanded TIL from surgically resected liver metastases of patients with CRC and characterized the phenotype and the prognostic value of expanded-CD4 T cells.

Methods: Liver metastases were surgically resected from 23 patients with CRC.

Echinococcus multilocularis vesicular fluid induces the expression of immune checkpoint proteins in vitro.

Aims: Alveolar echinococcosis is a severe chronic helminthic infection that mimics a tumour-like disease. This study aimed at investigating in vitro interactions between Echinococcus multilocularis vesicular fluid (VF) and different immune checkpoints (PD-1/PD-L1, CTLA-4, LAG-3 and TIM-3).

Methods And Results: Peripheral blood mononuclear cells (PBMC) from healthy blood donors were isolated by Ficoll.

CD28/4-1BB CD123 CAR T cells in blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is associated with a remarkably poor prognosis and with no treatment consensus. The identification of relevant therapeutic targets is challenging. Here, we investigated the immune functions, antileukemia efficacy and safety of CD28/4-1BB CAR T cells targeting CD123 the interleukin (IL)-3 receptor alpha chain which is overexpressed on BPDCN.

CD4 T cells target colorectal cancer antigens upregulated by oxaliplatin.

Immune checkpoint blockade has proven its efficacy in hypermutated subtypes of metastatic colorectal cancers (mCRC). Immunogenic potential can also be observed with conventional chemotherapies, but this property has never been explored thoroughly in CRC patients. The CRC therapeutic arsenal includes oxaliplatin, a well-characterized platinum drug already described as immunogenic.

Circulating NKp46 Natural Killer cells have a potential regulatory property and predict distinct survival in Non-Small Cell Lung Cancer.

Natural killer (NK) cells are innate effector lymphocytes widely involved in cancer immunosurveillance. In this study, we described three circulating NK cell subsets in patients with non-small cell lung cancer (NSCLC). Compared to healthy donors (HD), lower rate of the cytotoxic CD56 CD16 NK cells was found in NSCLC patients (76.

Personalized identification of tumor-associated immunogenic neoepitopes in hepatocellular carcinoma in complete remission after sorafenib treatment.

Sorafenib, a multi-targeted kinase inhibitor, is the current standard systemic treatment for advanced hepatocellular carcinoma. Sorafenib has anti-angiogenic and anti-proliferative properties and is also known to favor anti-tumor T cell responses by reducing the population of immunosuppressive cells such as Treg and MDSC. Anti-tumor immune responses, especially mediated by CD4+ T-cells, are critical for tumor cells eradication and therapies modulating those responses are appealing in a growing number of cancers.

Isolation and Characterization of an HLA-DRB1*04-Restricted HPV16-E7 T Cell Receptor for Cancer Immunotherapy.

High-risk human papillomavirus (HPV) infection is a causal factor in oropharyngeal and gynecological malignancies, and development of HPV-targeted immunotherapy could be used to treat patients with these cancers. T cell-mediated adoptive immunotherapy targeting E6 and E7, two HPV16 proteins consistently expressed in tumor cells, appears to be both attractive and safe. However, isolation of HPV-specific T cells is difficult owing to the low frequency of these cell precursors in the peripheral blood.

SALL4 oncogene is an immunogenic antigen presented in various HLA-DR contexts.

: To investigate the immunoprevalence of SALL4-derived peptides in healthy volunteers and cancer patients. : A multistep approach including prediction algorithms was used to design SALL4-derived peptides theoretically able to bind on common HLA-DR and HLA-A/B molecules. The presence of T-cell responses after a long term T-cell assay (28 days) against SALL4 was monitored in 14 healthy donors and the presence of T-cell responses after a short term T-cell assay (10 days) was monitored in 67 cancer patients using IFN-γ ELISPOT assay.

Echinococcus multilocularis vesicular fluid inhibits activation and proliferation of natural killer cells.

Alveolar echinococcosis is a severe chronic helminthic disease that mimics slow-growing liver cancer. The immune evasion strategy of Echinococcus multilocularis Leuckart, 1863 remains poorly understood. The aim of this study was to investigate in vitro the impact of E.

Identification of a novel PD-L1 positive solid tumor transplantable in HLA-A*0201/DRB1*0101 transgenic mice.

HLA-A*0201/DRB1*0101 transgenic mice (A2/DR1 mice) have been developed to study the immunogenicity of tumor antigen-derived T cell epitopes. To extend the use and application of this mouse model in the field of antitumor immunotherapy, we described a tumor cell line generated from a naturally occurring tumor in A2/DR1 mouse named SARC-L1. Histological and genes signature analysis supported the sarcoma origin of this cell line.

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T cells activation is a finely regulated process to establish an effective anti-infectious or antitumor immune response while avoiding harmful autoimmune reactions. Although T cells are considered to be the main protagonists of the antitumor immune response, they act in interaction with other immune cells. The meeting of naive T cells with dendritic cells induces their differentiation into effector cells following the recognition of the peptide-MHC complex by the T cell receptor.

Fungal peptides from pneumonitis hypersensitivity etiologic agents are able to induce specific cellular immune response.

Purpose: Hypersensitivity pneumonitis (HP) is an immunoallergic disease due to chronic exposure to high quantities of different microorganisms such as Mycobacterium immunogenum (Mi), a mycobacterium, and Lichtheimia corymbifera (Lc), a filamentous fungus. It has recently been demonstrated that the protein DLDH (dihydrolipoyl dehydrogenase), is common to these microorganisms. This study aimed to investigate the immune potential of overlapping peptide pools covering the MiDLDH and LcDLDH.

Heparan Sulfate Proteoglycans Promote Telomerase Internalization and MHC Class II Presentation on Dendritic Cells.

Telomerase is a prototype-shared tumor Ag and represents an attractive target for anticancer immunotherapy. We have previously described promiscuous and immunogenic HLA-DR-restricted peptides derived from human telomerase reverse transcriptase (hTERT) and referred as universal cancer peptide (UCP). In nonsmall cell lung cancer, the presence of spontaneous UCP-specific CD4 T cell responses increases the survival of chemotherapy-responding patients.

Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score.

In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS).

Immunoprevalence and magnitude of HLA-DP4 versus HLA-DR-restricted spontaneous CD4(+) Th1 responses against telomerase in cancer patients.

Cumulative evidence supports that CD4(+) Th1 cells play a key role in antitumor immunity. We previously reported the presence of spontaneous HLA-DR-restricted CD4(+) Th1 responses against telomerase reverse transcriptase (TERT) in various cancers by using promiscuous HLA-DR epitopes. Here, we described novel highly immunogenic HLA-DP4-binding epitopes from TERT named TERT541-555, TERT573-587, TERT613-627 and TERT911-925 and addressed the question about the immunoprevalence and magnitude of the naturally occurring antitumor CD4(+) T cell responses restricted by HLA-DP4 or HLA-DR, the two most common HLA class II.

IL-21-Induced MHC Class II+ NK Cells Promote the Expansion of Human Uncommitted CD4+ Central Memory T Cells in a Macrophage Migration Inhibitory Factor-Dependent Manner.

NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated.