A phase I/II study of telomerase peptide vaccination in combination with chemotherapy in patients with stage IV malignant melanoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 8031-8031 ◽  
Author(s):  
S. Aamdal ◽  
S. Dueland ◽  
O. Engebraaten ◽  
K. Owre ◽  
M. Dyrhaug ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Malignant Melanoma ◽  
Immune Responses ◽  
Phase I ◽  
Treatment Period ◽  
T Cell Response ◽  
Cytokine Profile ◽  
Skin Reactions

8031 Background: A phase I/II feasibility study was conducted to investigate the safety, tolerability and immunological response to vaccination with the telomerase peptide GV1001 (hTERT: 611–626) in combination with temozolomide (T). Methods: Twenty-five patients with malignant melanoma (15 stage M1c,10 stage M1b) received T day 1–5 every four weeks for 1–9 cycles. During the first cycle (4 weeks) they received i.d. injections of 560 μg GV1001 with local GM-CSF in week 2,3 and 4, followed by injections in week 6 and 7 in the second cycle and week 11 in the third cycle. The treatment period was 12 weeks (3 cycles). Booster vaccinations with 560 μg GV1001 were offered every third month. Monitoring of blood samples, clinical examination were performed regularly with radiological staging every 12th week. Immune responses were measured as DTH and in vitro T-cell proliferation. Results: The treatment was generally well tolerated with only grade 1–2 toxicity in most patients. Of 14 patients, 4 developed grade 3 toxicity and one grade 4 toxicity (neutropenia). Immune responses against GV1001 were detected in 17/21 patients (81%) at 12 weeks. Patients receiving up to 9 cycles of T exhibited stable proliferative responses to GV1001 throughout the treatment period. None of the patients had DTH response at trial entry and no DTH responses were observed in patients receiving T. This was not due to a shift in the cytokine profile since cloned GV1001-specific CD4+ T cells displayed a Th1 cytokine profile. Upon evaluation in week 12, 6 patients had SD, 10 PD. One patient had a PR with shrinkage or disappearance of multiple lung metastases. A patient continuing on vaccine alone developed significant DTH response when T therapy was stopped. Conclusions: Telomerase vaccination of patients receiving concomitant T treatment is feasible. The unexpected high proportion of patients showing an immune response indicates that regulatory T-cells may have been removed by T treatment. The chemotherapy may also have influenced effector cells required for development of skin reactions. In spite of lacking DTH response however, the majority of the patients demonstrated significant immune response indicating different regulation of DTH and T-cell response. No significant financial relationships to disclose.

scholarly journals Vaccination against RhoC induces long-lasting immune responses in patients with prostate cancer: results from a phase I/II clinical trial

2020 ◽  
Vol 8 (2) ◽  
pp. e001157
Author(s):  
Juliane Schuhmacher ◽  
Sonja Heidu ◽  
Torben Balchen ◽  
Jennifer Rebecca Richardson ◽  
Camilla Schmeltz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Cell Response ◽  
Small Gtpase ◽  
T Cell Response ◽  
Effector Memory ◽  
Tolerability Profile

BackgroundPeptide-based vaccination is a rational option for immunotherapy of prostate cancer. In this first-in-man phase I/II study, we assessed the safety, tolerability and immunological impact of a synthetic long peptide vaccine targeting Ras homolog gene family member C (RhoC) in patients with prostate cancer. RhoC is a small GTPase overexpressed in advanced solid cancers, metastases and cancer stem cells.MethodsTwenty-two patients who had previously undergone radical prostatectomy received subcutaneous injections of 0.1 mg of a single RhoC-derived 20mer peptide emulsified in Montanide ISA-51 every 2 weeks for the first six times, then five times every 4 weeks for a total treatment time of 30 weeks. The drug safety and vaccine-specific immune responses were assessed during treatment and thereafter within a 13-month follow-up period. Serum level of prostate-specific antigen was measured up to 26 months postvaccination.ResultsMost patients (18 of 21 evaluable) developed a strong CD4 T cell response against the vaccine, which lasted at least 10 months following the last vaccination. Three promiscuouslypresented HLA-class II epitopes were identified. Vaccine-specific CD4 T cells were polyfunctional and effector memory T cells that stably expressed PD-1 (CD279) and OX-40 (CD134), but not LAG-3 (CD223). One CD8 T cell response was detected in addition. The vaccine was well tolerated and no treatment-related adverse events of grade ≥3 were observed.ConclusionTargeting of RhoC induced a potent and long-lasting T cell immunity in the majority of the patients. The study demonstrates an excellent safety and tolerability profile. Vaccination against RhoC could potentially delay or prevent tumor recurrence and metastasis formation.Trial registration numberNCT03199872.

EBV-positive lymphoma patients have a selective deficiency in EBV immunity

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21032-21032
Author(s):  
K. N. Heller ◽  
P. G. Steinherz ◽  
C. S. Portlock ◽  
C. Münz
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Healthy Volunteers ◽  
Cell Response ◽  
T Cell Responses ◽  
T Cell Response ◽  
Specific Immune Response ◽  
Cell Responses

21032 Background: Epstein-Barr virus (EBV) asymptomatically establishes persistent infections in more than 90% of the adult population. However, due to effective immune control, only a minority of infected carriers develops spontaneous EBV-associated lymphomas. Since EBV nuclear antigen-1 (EBNA1) is the only protein expressed in all proliferating EBV infected cells we hypothesize that EBNA1 specific immune response is critical in preventing EBV-positive lymphomas. Methods: After informed consent, peripheral blood from healthy volunteers and lymphoma patients (prior to therapy- no evidence of cytopenia) were stimulated (ex vivo) with overlapping peptides covering the immunogenic EBNA1 (aa400–641) sequence. Frequency of EBNA1-specific T-cells were assessed by intracellular cytokine staining and flow cytometric proliferation assays. Cytokine pattern, surface marker phenotype and functional reactivity against EBV specific and control antigens were analyzed. Results: Patient and volunteer immune responses to control antigens and other viruses were assessed and statistically indistinguishable. EBNA1 specific CD4+ T cell responses were detected among 18 of 20 healthy carriers, and among 10 of 16 patients with EBV-negative lymphoma (relative to healthy volunteers p=0.145 via paired student T test). None of the patients with EBV-positive lymphomas (n=8) had a detectable EBNA1-specific CD4+ T-cell response (p<0.003 relative to healthy volunteers and patients with EBV-negative lymphomas). Conclusions: Healthy volunteers and patients with EBV-negative lymphoma have statistically similar EBNA1-specific CD4+ T cell responses. Although patients with EBV-positive lymphoma have intact immune responses to common viruses and antigens, they selectively lack an EBNA1-specific CD4+ T cell response. An intact EBNA1 specific immune response among patients with EBV-negaitve lymphoma implies that lymphoma is not a cause of a selective immune deficiency. On the contrary, these findings suggest that EBNA1-specific CD4+ T cells are critical in the prevention of EBV mediated lymphomas, and a defect in EBNA1 specific immunity may leave EBV carriers suseptible to EBV-positive lymphomas. EBNA1- specific CD4+ T cell function may be a new target for therapies of EBV-associated malignancies. No significant financial relationships to disclose.

scholarly journals Photochemical Internalization Enhanced Vaccination Is Safe, and Gives Promising Cellular Immune Responses to an HPV Peptide-Based Vaccine in a Phase I Clinical Study in Healthy Volunteers

2021 ◽  
Vol 11 ◽  
Author(s):  
Tone Otterhaug ◽  
Sylvia Janetzki ◽  
Marij J. P. Welters ◽  
Monika Håkerud ◽  
Anne Grete Nedberg ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Healthy Volunteers ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Humoral Immune ◽  
Photochemical Internalization ◽  
Vaccine Antigens

Background and AimsPhotochemical internalization (PCI) is a technology for inducing release of endocytosed antigens into the cell cytosol via a light-induced process. Preclinical experiments have shown that PCI improves MHC class I antigen presentation, resulting in strongly enhanced CD8+ T-cell responses to polypeptide antigens. In PCI vaccination a mixture of the photosensitizing compound fimaporfin, vaccine antigens, and an adjuvant is administered intradermally followed by illumination of the vaccination site. This work describes an open label, phase I study in healthy volunteers, to assess the safety, tolerability, and immune response to PCI vaccination in combination with the adjuvant poly-ICLC (Hiltonol) (ClinicalTrials.gov Identifier: NCT02947854).MethodsThe primary objective of the study was to assess the safety and local tolerance of PCI mediated vaccination, and to identify a safe fimaporfin dose for later clinical studies. A secondary objective was to analyze the immunological responses to the vaccination. Each subject received 3 doses of HPV16 E7 peptide antigens and two doses of Keyhole Limpet Hemocyanin (KLH) protein. A control group received Hiltonol and vaccine antigens only, whereas the PCI groups in addition received fimaporfin + light. Local and systemic adverse effects were assessed by standard criteria, and cellular and humoral immune responses were analyzed by ELISpot, flow cytometry, and ELISA assays.Results96 healthy volunteers were vaccinated with fimaporfin doses of 0.75–50 µg. Doses below 17.5 µg were safe and tolerable, higher doses exhibited local tolerability issues in some study subjects, mainly erythema, and pain during illumination. There were few, and only mild and expected systemic adverse events. The employment of PCI increased the number of subjects exhibiting a T-cell response to the HPV peptide vaccine about 10-fold over what was achieved with the antigen/Hiltonol combination without PCI. Moreover, the use of PCI seemed to result in a more consistent and multifunctional CD8+ T-cell response. An enhancement of the humoral immune response to KLH vaccination was also observed.ConclusionsUsing PCI in combination with Hiltonol for intradermal vaccination is safe at fimaporfin doses below 17.5 µg, and gives encouraging immune responses to peptide and protein based vaccination.

scholarly journals CD8+ T Cell Immune Response in Immunocompetent Mice during Zika Virus Infection

2017 ◽  
Vol 91 (22) ◽  
Author(s):  
Huarong Huang ◽  
Shihua Li ◽  
Yongli Zhang ◽  
Xiaojuan Han ◽  
Baoqian Jia ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Immune Responses ◽  
Zika Virus ◽  
Cell Response ◽  
T Cell Response ◽  
Cell Immune Response ◽  
Zikv Infection

ABSTRACT Zika virus (ZIKV) infection causees neurologic complications, including Guillain-Barré syndrome in adults and central nervous system (CNS) abnormalities in fetuses. We investigated the immune response, especially the CD8+ T cell response in C57BL/6 (B6) wild-type (WT) mice, during ZIKV infection. We found that a robust CD8+ T cell response was elicited, major histocompatibility complex class I-restricted CD8+ T cell epitopes were identified, a tetramer that recognizes ZIKV-specific CD8+ T cells was developed, and virus-specific memory CD8+ T cells were generated in these mice. The CD8+ T cells from these infected mice were functional, as evidenced by the fact that the adoptive transfer of ZIKV-specific CD8+ T cells could prevent ZIKV infection in the CNS and was cross protective against dengue virus infection. Our findings provide comprehensive insight into immune responses against ZIKV and further demonstrate that WT mice could be a natural and easy-access model for evaluating immune responses to ZIKV infection. IMPORTANCE ZIKV infection has severe clinical consequences, including Guillain-Barré syndrome in adults, microcephaly, and congenital malformations in fetuses and newborn infants. Therefore, study of the immune response, especially the adaptive immune response to ZIKV infection, is important for understanding diseases caused by ZIKV infection. Here, we characterized the CD8+ T cell immune response to ZIKV in a comprehensive manner and identified ZIKV epitopes. Using the identified immunodominant epitopes, we developed a tetramer that recognizes ZIKV-specific CD8+ T cells in vivo, which simplified the detection and evaluation of ZIKV-specific immune responses. In addition, the finding that tetramer-positive memory CD8+ T cell responses were generated and that CD8+ T cells can traffic to a ZIKV-infected brain greatly enhances our understanding of ZIKV infection and provides important insights for ZIKV vaccine design.

Cytokine profile of sipuleucel-T (sip-T) in differentiating reactivation of latent immunity from de novo immune responses.

2017 ◽  
Vol 35 (7_suppl) ◽  
pp. 163-163
Author(s):  
Charles G. Drake ◽  
Daniel Peter Petrylak ◽  
Emmanuel S. Antonarakis ◽  
Adam S. Kibel ◽  
Nancy N. Chang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
De Novo ◽  
T Cell Response ◽  
Cytokine Profile ◽  
Castration Resistant Prostate Cancer ◽  
Ifn Γ

163 Background: Sip-T is an FDA-approved immunotherapy for treating patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). It is manufactured from autologous peripheral blood mononuclear cells (PBMCs) cultured with PA2024, a fusion of prostatic acid phosphatase (PAP) and granulocyte macrophage colony-stimulating factor. Survival of sip-T–treated mCRPC pts correlates with immune responses to PA2024 and/or PAP. PA2024- or PAP-specific CD4+ and CD8+ T cell proliferation and cytokine production and release were assessed to better understand sip-T–induced T cell responses. Methods: Pts with biochemical recurrence or mCRPC were from sip-T trials (NCT01431391, NCT01981122). PBMCs collected at baseline through 6 mo post–sip-T were cultured in vitro and stimulated with PA2024 or PAP. CD4+ and CD8+ T cells were assessed (n=19) for proliferation and intracellular IL-2 and IFN-γ. The cytokine profile was confirmed in supernatant with a meso scale discovery assay. P<0.10 was statistically significant. Results: Compared with baseline, PA2024-specific proliferating CD4+ and CD8+ T cells had increased intracellular IL-2 and IFN-γ levels at wk 6 and mo 6, with a similar trend for PAP-specific proliferating T cells (Table 1). Compared with unstimulated controls, a significant >2-fold increase in PA2024-stimulated IL-2 and IFN-γ in supernatant was observed at wk 6 and mo 6 over baseline (p<0.001). PAP-stimulated IL-2 and IFN-γ supernatant levels increased over baseline and were significantly elevated for IFN-γ at wk 6 (p<0.10). Conclusions: Sip-T therapy generated a de novo PA2024-specific T cell response, as indicated by the cytokine release profile. The PAP-stimulated cytokine profile suggests that pre-existing immunity with terminally differentiated T cells are expanded. Thus, sip-T reactivated an anti-PAP response in memory T cells, thereby overcoming immunosuppressive mechanisms in PC. Clinical trial information: NCT01431391; NCT01981122. [Table: see text]

Personalized viral-based prime/boost immunotherapy targeting patient-specific or shared neoantigens: Immunogenicity, safety, and efficacy results from two ongoing phase I studies.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3137-3137
Author(s):  
Charles G. Drake ◽  
Melissa Lynne Johnson ◽  
Alexander I. Spira ◽  
Gulam Abbas Manji ◽  
David Paul Carbone ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Cell Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Patient Specific ◽  
Clinical Activity ◽  
Skin Reactions ◽  
Phase I Studies

3137 Background: Neoantigens are key targets of a tumor-specific immune response and CD8 T cells targeting neoantigens drive clinical benefit in patients (pts) treated with checkpoint inhibitors. Methods: Two Phase I studies are being conducted to assess the safety, immunogenicity, and early clinical activity of a viral-based neoantigen-targeting prime/boost immunotherapy aimed at maximizing the CD8 T cell response. Both studies use a chimpanzee adenovirus prime followed by increasing doses of repeat boosts with a self-amplifying mRNA in combination with IV nivolumab +/- SC ipilimumab. In the first study, GO-004, patient-specific neoantigens are predicted using Gritstone's EDGE model and incorporated into both prime/boost vectors. In GO-005, shared neoantigens derived from common driver mutations (including several from KRAS) are encoded in off-the-shelf prime/boost vectors. Results: To date, 12 pts have been treated: 6 pts with GEA, NSCLC, or MSS-CRC (GO-004) and 6 pts with NSCLC, MSS-CRC, or PDA (GO-005) with all pts receiving IV nivolumab and 5 pts also receiving SC ipilimumab. Nine pts continue to receive study treatment. No DLTs have been observed. Treatment-related AEs are reversible and include Grade 1/2 fever (7/12), injection site reactions (4/12), fatigue (3/12), diarrhea (2/12), hypotension (2/12), pruritus (2/12), skin reactions (2/12), anorexia (1/12), dyspnea (1/12), hyponatremia (1/12), infusion-related reactions (1/12), myalgia (1/12), and asymptomatic Grade 3 CK elevation (1/12). At the time of analysis, 8 of 12 pts with ≥ 1 radiographic assessment have a best response of stable disease (SD) (3) and progressive disease (PD) (4), and one pt with no evaluable disease at baseline continues on study > 8 months. In GO-005, 1 pt with SD has a 20% reduction in tumor dimensions that correlates with a decrease in ctDNA. In 4 pts in GO-004 analyzed to date, all pts showed substantial neoantigen-specific CD8 T cell responses to multiple neoantigens after priming which increase further in 2 of 3 pts analyzed after subsequent boosts. In GO-005, 1 of 3 pts showed a robust KRAS G12C-specific CD8 T cell response. Induced T cells express IFNg and granzyme B, consistent with an effector response. Conclusions: Taken together, these early data support the tolerability of a viral-based prime/boost immunotherapy, demonstrate marked immunogenicity, and are consistent with potential clinical activity. Additional pts and data at higher dose levels will be presented. Clinical trial information: NCT03639714, NCT03953235 .

Abstract 171: T Cell Mediated Immune Responses Regulate Cardiac Remodeling and Survival in Pressure Overload Induced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Pilar Alcaide ◽  
Tania Nevers ◽  
Ane Salvador ◽  
Anna Grodecki-Pena ◽  
Andrew Knapp ◽  
...  
Keyword(s):  
Gene Expression ◽  
Heart Failure ◽  
Immune Response ◽  
T Cells ◽  
Endothelial Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cardiac Remodeling ◽  
Pressure Overload ◽  
T Cell Response

Background: Clinical data support that inflammation and the improper regulation of the immune response are intimately associated with Heart Failure (HF), however, the type of immune response involved and whether it regulates cardiac remodeling remains largely unexplored. We hypothesize that T cell mediated immune responses and their recruitment into the heart influence cardiac remodeling and contribute to the pathogenesis of pressure overload induced HF. Methods and Results: Using quantitative flow cytometry we found that T cells infiltrated the heart as Wild-type mice (WT) developed systolic dysfunction and LV hypertrophy in response to transverse aortic constriction (TAC) (p<0.01 TAC vs Sham). Real time imaging demonstrated that T cells from TAC mice adhered to activated heart endothelial cells in higher numbers than T cells from Sham mice under physiological flow conditions in vitro (P<0.05) indicating a systemic T cell activation to pressure overload induced by TAC. Similarly, circulating T cells from patients with HF adhered more to activated human umbilical vein endothelial cells (HUVEC) than T cells from healthy volunteers. Based on these findings, we performed similar TAC studies in T cell deficient mice (TCRα -/- ). In contrast with WT TAC mice, TCRα -/- had preserved LV systolic and diastolic function (p<0.01) determined by echocardiography and hemodynamic studies, reduced LV fibrosis (p<0.001) and TGFβ1, collagen Iα and αSMA gene expression (p<0.05), and reduced LV hypertrophy and gene expression of ANP and BNP (p<0.05), but unaltered expression of SerCA. Remarkably, TCRα -/- had improved survival after 4 weeks of TAC [100%(16/16) TCRα -/- vs 73.7%(14/19) WT, p=0.023]. Ongoing studies will determine the mechanisms regulating T cell recruitment into the heart, the type of T cell response involved and its contribution to pathological remodeling of the heart. Conclusion: Our studies demonstrate that T cell immune responses and their recruitment into the LV contribute to the pathogenesis of pressure overload induced HF by mechanisms involving T cell regulation of cardiac hypertrophy and fibrosis, and open a window to develop novel therapeutic strategies to improve the structural, functional and molecular deficits of the failing heart.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals 596 Combining Bempegaldesleukin (CD122-preferential IL-2 pathway agonist) and NKTR-262 (TLR7/8 agonist) pairs local innate activation with systemic CD8+ T cell expansion to enhance anti-tumor immunity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A626-A626
Author(s):  
Annah Rolig ◽  
Daniel Rose ◽  
Grace Helen McGee ◽  
Saul Kivimae ◽  
Werner Rubas ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Immune Responses ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cycle Phase ◽  
Tumor Cell Death ◽  
Specific Immunity

BackgroundTumor cell death caused by radiation therapy (RT) can trigger anti-tumor immune responses in part because dying cells release adjuvant factors that amplify and sustain DC and T cell responses. We previously demonstrated that bempegaldesleukin (BEMPEG:NKTR-214, a first-in-class CD122-preferential IL-2 pathway agonist), significantly enhanced the anti-tumor efficacy of RT through a T cell-dependent mechanism. Because RT can induce either immunogenic or tolerogenic cell death, depending on a multitude of factors (radiation dose, cell cycle phase, and tumor microenvironment), we hypothesized that providing a specific immunogenic adjuvant, like intratumoral NKTR-262, a novel toll-like receptor (TLR) 7/8 agonist, to the tumor site would further improve systemic tumor-specific immunity by promoting synergistic activation of local immunostimulatory innate immune responses. Therefore, we evaluated whether intratumoral NKTR-262, combined with systemic BEMPEG treatment would result in improved tumor-specific immunity and survival compared to BEMPEG combined with RT.MethodsTumor-bearing mice (CT26; EMT6) received BEMPEG (0.8 mg/kg; iv), RT (16 Gy x 1), and/or intratumoral NKTR-262 (0.5 mg/kg). Flow cytometry was used to evaluate CD4+ and CD8+ T cell activation status in the blood and tumor (7 days post-treatment). The contribution of specific immune subsets was determined by depletion of CD4+, CD8+, or NK cells. CD8+ T cell cytolytic activity was determined in vitro with an Incucyte assay. Data are representative of 1–2 independent experiments (n=5–14/group) and statistical significance was determined by 1-way ANOVA (p-value cut-off of 0.05).ResultsBEMPEG/NKTR-262 resulted in significantly improved survival compared to BEMPEG/RT. Both combination therapies were CD8+ T cell dependent. However, response to BEMPEG/NKTR-262 was characterized by a significant expansion of activated CD8+ T cells (GzmA+; Ki-67+; ICOS+; PD-1+) in the blood, which correlated with reduced tumor size (p<0.05). In the tumor, BEMPEG/NKTR-262 induced higher frequencies of GzmA+ CD8+ T cells exhibiting reduced expression of suppressive molecules (PD-1+, TIM-3+), compared to BEMPEG/RT. Additionally, CD8+ T cells isolated from BEMPEG/NKTR-262-treated tumors had greater cytolytic capacity than those from BEMPEG/RT-treated mice.ConclusionsCombining BEMPEG with NKTR-262 lead to a more robust expansion of activated CD8+ T cells compared to the BEMPEG/RT combination. Enhancement of the activated CD8+ T cell response in mice treated with NKTR-262 in combination with BEMPEG suggests that intratumoral TLR stimulation provides superior antigen presentation and costimulatory activity compared to RT. A clinical trial of BEMPEG/NKTR-262 for patients with metastatic solid tumors is in progress (NCT03435640).

scholarly journals Identification of leptospiral protein antigens recognized by WC1+ γδ T cell subsets as target for development of recombinant vaccines

2021 ◽  
Author(s):  
Aline Teixeira ◽  
Alexandria Gillespie ◽  
Alehegne Yirsaw ◽  
Emily Britton ◽  
Janice Telfer ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Outer Membrane Proteins ◽  
Γδ T Cells ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Economic Losses ◽  
Γδ T Cell ◽  
Protein Antigens

Pathogenic Leptospira species cause leptospirosis, a neglected zoonotic disease recognized as a global public health problem. It is also the cause of the most common cattle infection that results in major economic losses due to reproductive problems. γδ T cells play a role in the protective immune response in livestock species against Leptospira while human γδ T cells also respond to Leptospira. Thus, activation of γδ T cells has emerged as a potential component for optimization of vaccine strategies. Bovine γδ T cells proliferate and produce IFN-γ in response to vaccination with inactivated leptospires and this response is mediated by a specific subpopulation of the WC1-bearing γδ T cells. WC1 molecules are members of the group B scavenger receptor cysteine rich (SRCR) superfamily and are composed of multiple SRCR domains, of which particular extracellular domains act as ligands for Leptospira. Since WC1 molecules function as both pattern recognition receptors and γδ TCR coreceptors, the WC1 system has been proposed as a novel target to engage γδ T cells. Here, we demonstrate the involvement of leptospiral protein antigens in the activation of WC1+ γδ T cells and identified two leptospiral outer membrane proteins able to interact directly with them. Interestingly, we show that the protein-specific γδ T cell response is composed of WC1.1+ and WC1.2+ subsets, although a greater number of WC1.1+ γδ T cells respond. Identification of protein antigens will enhance our understanding of the role γδ T cells play in the leptospiral immune response and in recombinant vaccine development.

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