CTLA-4 In Patients Research Articles

Effect of Concurrent Chemoradiotherapy on Regulatory T Cells,CD8/Treg Ratio,PD1 and CTLA-4 in Patients with Cervical Cancer

To investigate the significance of chemoradiotherapy on regulatory T (Treg) cells, CD8 / Treg ratio, squamous cell carcinoma antigen (SCC), PD1, and CTLA-4 in the peripheral blood of cervical cancer (CC)patients. A retrospective study was performed 56 cervical cancer patients treated with concurrent chemoradiotherapy from September 06, 2019 to April 19, 2021 were selected, in patients who underwent surgery. Flow cytometry was used to determine the levels of regulatory T cells, CD8 / Treg ratio, squamous cell carcinoma antigen, PD1, and CTLA-4 in the peripheral blood of patients before and after concurrent therapy, Differences in relative level values before and after treatment were calculated using statistical protocols such as the paired samples t-test. The proportion of CD4+CD25+CD127low Treg in CD4+T cells was (15.96±4.29) % in cervical cancer patients and (9.76±4.21) % in healthy controls, and the difference between the two groups was statistically significant (P < 0.05). In different age groups, Treg, CD8 levels, CD4/CD8 ratio and CD8/Treg ratio before and after radiotherapy and chemotherapy had no significant relationship with age and pathological types (P > 0.05), but CD8/Treg ratio was higher in patients with adenocarcinoma than in patients with squamous cell carcinoma after radiotherapy and chemotherapy, and the difference was statistically significant (Z = -2.076 P = 0.038). For postoperative patients, CD8 levels were lower before and after chemoradiotherapy than after chemoradiotherapy (T = -2.320 P = 0.020). In terms of PD1, regardless of age, pathological type, the level of PD1 after radiotherapy and chemotherapy was higher than that before chemotherapy, and the difference was statistically significant. The level of adenocarcinoma (53.50±10.16) % was significantly higher than that of squamous carcinoma (43.72±11.89) % (T = -2.609 P = 0.011). The PD1 level of patients with cervical cancer radical resection (41.64±13.29) % was lower than that of patients without cervical cancer radical resection (46.84±10.61) %, the difference was statistically significant (T = 2.187 P = 0.031). The PD1 level of patients without pelvic lymph node metastasis (48.84±10.04) was significantly higher than that of patients with pelvic lymph node metastasis (42.96±10.85), and the difference was statistically significant (T = -2.019 P = 0.049), There were no significant differences in vascular positivity, invasion depth, stump positivity, pelvic lymph node positivity and Treg level, CD8 level, CTLA4 level, SCC, CD4/CD8 ratio, CD8/Treg ratio (ALL P > 0.05). The level of Treg cells in patients with cervical cancer is significantly higher than that in healthy people, and it does not decrease immediately after radiotherapy and chemotherapy. Peripheral blood Treg, PD1, CD8 and CD8/Treg can reflect the immune function of the body, which may provide a certain reference for immunotherapy.

Abstract PR016: Systemic T cell metabolic and effector function changes following treatment with PD1 and CTLA4 in patients with kidney cancer

Abstract Background: We have previously shown that dysfunctional renal cell carcinoma (RCC) tumor infiltrating lymphocytes (TIL) have glycolytic insufficiencies, and effector function can be rescued by bypassing glycolysis and modulating mitochondrial fitness (Beckermann et al., 2020). We have also shown that RCC TIL biology may be captured in a subset of the peripheral blood T cells, providing an opportunity to assess the tumor immune landscape in noninvasive liquid biopsy from peripheral blood samples (Siska et al., 2018). Methods: We evaluated the peripheral blood of twenty patients with RCC undergoing systemic therapy with PD1 and CTLA4, ten of whom had primary progressive disease and ten who had clinical benefit (SD, PR, CR for 6 months or greater), studying samples before and after three weeks on treatment. Single Cell mRNA gene expression and TCR clonal analysis was assessed in a subset of patients as well as ArcherDx V(D)J sequencing on matched tumor tissue. To assess the impact of mitochondrial membrane potential on T cell responses in patients with ccRCC we flow sorted viable, CD3+ PBMCs with high or low mitochondrial potential. The peripheral blood was analyzed for protein changes using a 44-plex labeled CyTOF antibody panel focused on T cells surface markers, as well as effector and metabolic function. Results: From peripheral blood of patients with ccRCC we find that CD3+ T cells are predominantly composed of subgroups with mitochondrial high membrane potential and expand in number after αPD1+αCTLA4 therapy. Peripheral T cells with low mitochondrial membrane potential are enriched for gene expression pathways associated with cytotoxicity. T cells with mitochondrial low potential also tended to have oligoclonal TCR expansion that were frequently shared between tumor and blood compared to that of mitochondrial high potential T cells. Mitochondrial low T cells were enriched for genes associated with cytotoxicity including CTSW, CD8, KLRK1, and KLRD. The tumor T cell repertoire demonstrated the greatest similarity with peripheral T cells that had low mitochondrial membrane potential. Shared T cells between the tumor and periphery are enriched for chemotaxis, antigen binding, and cytotoxicity signaling pathways. At the protein level, patients with response have lower metabolic activity and greater CD4+ effector T cells, consistent with the scRNA-seq data, while patients with progressive disease have more metabolically active profiles. Conclusions: Single cell gene expression and mass cytometry analysis shows that systemic changes occur in patients with kidney cancer undergoing αPD1 and αCTLA4 treatment. Shared TCR from TIL exist in oligoclonally expanded T cells in the peripheral blood. These shared T cells are enriched in subsets with low mitochondrial membrane potential and express markers of effector function and upregulate cytotoxic T cell pathways. Citation Format: Dalton Greenwood, Paul Lindau, Caroline Roe, Madelyn Landis, Rachel Hongo, Brian Rini, Jonathan Irish, W. Kimryn Rathmell, Jeffrey Rathmell, Kathryn Beckermann. Systemic T cell metabolic and effector function changes following treatment with PD1 and CTLA4 in patients with kidney cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Kidney Cancer Research; 2023 Jun 24-27; Austin, Texas. Philadelphia (PA): AACR; Cancer Res 2023;83(16 Suppl):Abstract nr PR016.

16P KRAS and CTLA-4 expression profiling in circulating tumor cells in patients with colorectal cancers

Circulating tumour cells (CTCs) could escape the host immune surveillance by altering the expression of immune regulatory molecules (PD-L1, PD-L2, CTLA-4, CD47) in cancer patients. Recent studies suggested that KRAS mutation might promote the immune escape of tumour cells by inducing the upregulation of these molecules. However, the regulatory effects of KRAS on the expression of CTLA-4 in patients with colorectal cancer (CRC) have yet to be explored. This study aimed to investigate KRAS and CTLA-4 mRNA expression profiling in CTCs from patients with CRC.

A phase I, first-in-human, open label, dose-escalation and cohort expansion study of MGD019, a bispecific DART protein binding PD-1 and CTLA-4 in patients with unresectable or metastatic neoplasms.

TPS2661 Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.

Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

Double Immune Checkpoint Inhibitor Blockade with Nivolumab and Ipilimumab with or without Azacitidine in Patients with Myelodysplastic Syndrome (MDS)

338 NK CELL SECRETED IFN-g BLOCKS HCV REPLICATION AND MAY PROMOTE SPONTANEOUS CLEARANCE OF ACUTE HEPATITIS C IN HIV(+) PATIENTS

are associated with antiviral effector T-cell dysfunction, which influences on T-cell exhaustion and persistent viral infection. These PD-1 and CTLA-4 are up-regulated in chronic viral infection such as chronic hepatitis C, chronic hepatitis B and human immunodeficiency virus infection but there is no report about the role of PD-1 and CTLA-4 in patients with symptomatic acute hepatitis A. We investigated the expression of PD-1 and CTLA-4 during symptomatic and convalescent phases of acute hepatitis A. Methods: Seven patients with symptomatic acute hepatitis A, 5 patients with non-viral acute toxic hepatitis were enrolled for detection of PD-1 and CTLA-4 on T-cell subset of peripheral blood mononuclear cells (PBMC) isolated from these subjects during symptomatic and convalescent phases by flow cytometry. Five as healthy control were also examined for comparison with these patients. Results: Symptomatic acute hepatitis A showed significant increase of PD-1 and CTLA-4 expression compared to non-viral acute toxic hepatitis or healthy control (PD-1; 18.3±15.7% vs. 3.7±3.0% vs. 1.6±1.8%, p < 0.05, CTLA-4; 23.5±12.0% vs. 6.1±1.2% vs. 5.9±1.2%, p < 0.05) (median ± SD). In addition, highly expressed PD-1 and CTLA-4 were dramatically decreased in convalescent phase of acute hepatitis A. Conclusions: In acute hepatitis A, PD-1 and CTLA-4 are upregulated during symptomatic phase then down-regulated after recovery. This changing pattern of PD-1 and CTLA-4 expression was not seen in non-viral acute toxic hepatitis. Our findings suggest that PD-1 and CTLA-4 have protective effect as inhibitory molecules to suppress cytotoxic T-cells which induce destruction of viral infected hepatocytes.

CTLA‐4 expression in T cells of patients with atopic dermatitis

Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is a surface molecule of activated T cells with sequence homologous to CD28, and may act as a negative regulator of T-cell activation. In murine animal models, cross-linkage of CTLA-4 molecules on the cell surface results in decreased T-cell proliferation, accompanied by increased interleukin (IL)-2 production and apoptosis. To clarify the activation of peripheral blood T cells, we studied the CTLA-4 expression in 32 patients with atopic dermatitis who visited our institution, and 19 normal children who visited for pre-operative laboratory examination were used as normal controls. Whole blood was obtained from all subjects and stained with anti-CD3, anti-CD4, anti-CD8 monoclonal antibodies (mAb). After erythrocyte lysis with lysing solution, the cells were stained with anti-CTLA-4 mAb, and stained cells were analysed by fluorescence-activated cell sorter (FACScan) flow cytometer. Intracellular expression of CTLA-4 was significantly upregulated in peripheral blood CD3+ T cells (36.8%), CD4+ T cells (21.7%) and CD8+ T cells (18.7%) of patients with atopic dermatitis, compared with normal control (18.3%, 9.7%, 9.8%; respectively). Furthermore, CTLA-4-positive CD3+ T cells in patients with severe atopic dermatitis were significantly higher compared with milder group (42.8% vs. 32.2%). However, no significant difference was obtained in CD4+ and CD8+ T cells. Mean percentage of T cells expressing CTLA-4 in patients with atopic dermatitis was higher than the control group. These observations suggest the possibility that the disease activity can be correlated with the CTLA-4 level.

Cutting Edge: A Soluble Form of CTLA-4 in Patients with Autoimmune Thyroid Disease

We have recently identified a novel transcript of the CTLA-4 gene that may represent a native soluble form of CTLA-4 (sCTLA-4). To determine whether sCTLA-4 was expressed in humans, we applied a sensitive enzyme immunoassay on serum from patients with autoimmune thyroid disease (ATD). Eleven of 20 patients with ATD had circulating levels of sCTLA-4 ranging from 28 to 78 ng/ml, whereas only 1 of 30 apparently healthy volunteers had a level greater than 4 ng/ml. sCTLA-4 immunoreactivity was inhibited by its binding to B7.1, suggesting that sCTLA-4 is a functional receptor. Immunoprecipitation analysis of serum from patients with ATD revealed a polypeptide consistent with the predicted size of sCTLA-4. We conclude that a native soluble form of CTLA-4 is derived from an alternate transcript of the CTLA-4 gene, and its level in plasma is elevated among a population of patients with ATD.