Gastrin vaccine and immune checkpoint antibody therapy for pancreatic cancer.

259 Background: Pancreatic cancer is poorly responsive to therapy due to fibrosis in the tumor microenvironment and nonspecificity of treatments. The peptide gastrin stimulates growth of pancreatic cancer in an autocrine fashion. Polyclonal Antibody Stimulator (PAS) is a gastrin vaccine that in clinical trials prolongs survival of patients who develop neutralizing gastrin antibodies. We hypothesized that PAS also elicits a memory and T-cell response that would improve effectiveness of immune checkpoint antibodies. Methods: C57BL/6 mice were injected sc with syngeneic mT3 murine pancreatic cancer cells. After 1 week (tumors evident), groups were treated with PBS (control); PAS (100 μg or 250 μg); PD-1 antibody (150 μg); or combined therapy with PAS100/PD-1. PAS was given ip at weeks 0, 1 and 3. Anti-PD-1 was given on days 0, 4, 8, 15 and 21. On day 31 spleens were collected for T-cell surface analysis and cytokine activation by flow cytometry. Tumors were stained for fibrosis and with immunohistochemical stains for CD8+ and FoxP3+ tumor infiltrating lymphocytes (TILs). Results: PAS resulted in T-cell activation; however, the portion of terminally differentiated effector memory double negative T-cells (CD4- CD8-) in CD3+cells from mice treated with the combination PAS100/PD-1 was two-fold higher than those portions from mice treated with PBS, PD-1 or PAS100. Lymphocytes from PAS-treated mice elicited cytokine release (Interferon-γ, granzyme, perforin, and TNF-α) upon re-stimulation with gastrin in vitro, whereas PAS100/PD-1-treated mice show the highest endogenous cytokines levels. PAS250 monotherapy decreased tumor growth. Neither PAS100 nor anti-PD-1 monotherapy decreased tumor size, but combination PAS100/PD-1 antibody tumors were smaller, had less fibrosis, fewer T-regulatory lymphocytes, and increased CD8+ TILs. Conclusions: In addition to eliciting a B-cell response, PAS activates T-lymphocytes rendering tumors susceptible to immune checkpoint antibody treatment. Smaller tumors with combined therapy may be due to the anti-fibrotic effect of PAS on the tumor microenvironment and changes in CD8+ TILs. This study supports that PAS is an important immunotherapy that elicits both B- and T-cell anti-cancer responses.

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Inhibition of arginase modulates T-cell response in the tumor microenvironment of lung carcinoma

OncoImmunology ◽

10.1080/2162402x.2021.1956143 ◽

2021 ◽

Vol 10 (1) ◽

pp. 1956143

Author(s):

Anna Sosnowska ◽

Justyna Chlebowska-Tuz ◽

Pawel Matryba ◽

Zofia Pilch ◽

Alan Greig ◽

...

Keyword(s):

T Cell ◽

Tumor Microenvironment ◽

Lung Carcinoma ◽

Cell Response ◽

T Cell Response

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

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001157 ◽

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.

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312P Identification of neoantigen-specific T cell response and anti-tumour immunity in pancreatic cancer

Annals of Oncology ◽

10.1016/j.annonc.2020.10.306 ◽

2020 ◽

Vol 31 ◽

pp. S1363-S1364

Author(s):

X. Du ◽

W. Lin ◽

X. Lyu ◽

Y. Huang ◽

K. He ◽

...

Keyword(s):

Pancreatic Cancer ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

Tumour Immunity

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Delayed acute allograft rejection in elderly recipients is associated with impaired effector/memory t-cell response

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2010.06.160 ◽

2010 ◽

Vol 211 (3) ◽

pp. S62

Author(s):

Damanpreet Singh Bedi ◽

Christian Denecke ◽

Xupeng Ge ◽

Irene K. Kim ◽

Anke Jurisch ◽

...

Keyword(s):

T Cell ◽

Cell Response ◽

Allograft Rejection ◽

T Cell Response ◽

Effector Memory ◽

Acute Allograft Rejection ◽

Memory T Cell ◽

Elderly Recipients

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VXM01, an oral T-cell vaccine targeting the tumor vasculature: Results from a randomized, controlled, first-in-man study in pancreatic cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.3090 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 3090-3090 ◽

Cited By ~ 2

Author(s):

Friedrich Hubertus Schmitz-Winnenthal ◽

Lars Grenacher ◽

Tobias Friedrich ◽

Heinz Lubenau ◽

Marco Springer ◽

...

Keyword(s):

Pancreatic Cancer ◽

Placebo Group ◽

T Cell ◽

Cell Response ◽

T Cell Responses ◽

T Cell Response ◽

Adverse Event Rate ◽

Tumor Perfusion ◽

Dce Mri ◽

Cell Responses

3090 Background: VXM01 is an orally available, bacterially transmitted DNA vaccine targeting VEGFR-2. Pre-clinically, VXM01 showed anti-tumor activity in multiple tumor types. This first-in-human study was designed to evaluate the safety and tolerability of VXM01. Secondary endpoints included VEGFR-2 specific T-cell responses, tumor perfusion changes, and related biomarkers. Methods: A randomized, double-blinded, placebo-controlled, dose-escalation study was conducted in 45 patients with advanced pancreatic cancer. VXM01 or placebo was given on days 1, 3, 5, and 7. Doses were escalated from 10(6) CFU to 10(10) CFU over 5 dose groups, each including 6 VXM01 and 3 placebo patients. VEGFR-2 specific T-cell activity was monitored by ELISpot and T(reg) specificity assays before, during and after the vaccination course. Tumor perfusion was assessed by DCE-MRI on days 0 and 38. Biomarkers included CA19-9, VEGF-A and collagen IV. Results: Patients were enrolled from 12/2011 to 10/2012. Most commonly observed AEs were leukopenia, abdominal pain, and diarrhea, which were all equally distributed between treatment and placebo group. While a mild elevation in average blood pressure was observed in the VXM01 group over the placebo group, the hypertension adverse event rate did not differ between both groups. No DLTs were observed. VEGFR-2 specific effector T-cell response was increased in 57% of evaluable VXM01 treated patients, during and after the vaccination course. In 25% of the VXM01 group, the T-cell response score post-vaccination was higher than maximum placebo levels. In contrast, VEGFR-2 specific T(reg) responses were overall reduced in vaccinated patients. DCE-MRI data indicated a >33% drop in K(trans)/tumor perfusion in 35% of evaluable VXM01 treated patients vs. 10% in the placebo group. Mean changes were -4% (VXM01) and +15% (placebo). Reduced tumor perfusion correlated with VEGFR-2 specific T-cell responses and biomarker responses. Conclusions: VXM01 appeared safe and was well tolerated without DLTs across 5 tested dose levels. The data suggest further that VXM01 induces and enhances a VEGFR-2 specific T-cell response and impacts tumor perfusion. Clinical trial information: ISRCTN68809279.

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Magnitude and quality of tumor-infiltrating T-cell response upon poxvirus-based active immunotherapy alone and in combination with CTLA-4 immune checkpoint inhibition.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.3013 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 3013-3013

Author(s):

Susan P Foy ◽

Stefanie J Mandl ◽

Tracy dela Cruz ◽

Joseph Cote ◽

Evan Gordon ◽

...

Keyword(s):

T Cell ◽

Immune Checkpoint ◽

Cell Response ◽

T Cell Response ◽

Active Immunotherapy ◽

Checkpoint Inhibition ◽

Immune Checkpoint Inhibition

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Children and adults with mild COVID-19 symptoms develop memory T cell immunity to SARS-CoV-2

10.1101/2021.09.10.21263333 ◽

2021 ◽

Author(s):

Patricia Kaaijk ◽

Veronica Olivo Pimentel ◽

Maarten E. Emmelot ◽

Martien Poelen ◽

Alper Cevirgel ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cell Response ◽

T Cell Response ◽

T Cell Immunity ◽

Immune Memory ◽

Effector Memory ◽

Longitudinal Assessment ◽

Memory T Cell ◽

Cell Immunity

Background: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has led to considerable morbidity/mortality worldwide, but most infections, especially among children, have a mild course. However, it remains largely unknown whether infected children develop cellular immune memory. Methods: To determine whether a memory T cell response is being developed as an indicator for long-term immune protection, we performed a longitudinal assessment of the SARS-CoV-2-specific T cell response by IFN-γ ELISPOT and activation marker expression analyses of peripheral blood samples from children and adults with mild-to-moderate COVID-19. Results: Upon stimulation of PBMCs with heat-inactivated SARS-CoV-2 or overlapping peptides of spike (S-SARS-CoV-2) and nucleocapsid proteins, we found S-SARS-CoV-2-specific IFN-ɣ T cell responses in most infected children (83%) and all adults (100%) that were absent in unexposed controls. Frequencies of SARS-CoV-2-specific T cells were higher in infected adults, especially in those with moderate symptoms, compared to infected children. The S-SARS-CoV-2 IFN-ɣ T cell response correlated with S1-SARS-CoV-2-specific serum IgM, IgG, and IgA antibody concentrations. Predominantly, effector memory CD4+ T cells of a Th1 phenotype were activated upon exposure to SARS-CoV-2 antigens, which persisted for 4-8 weeks after symptom onset. We detected very low frequencies of SARS-CoV-2-reactive CD8+ T cells in these individuals. Conclusions: Our data indicate that an antigen-specific memory CD4+ T cell response is induced in children and adults with mild SARS-CoV-2 infection. T cell immunity induced after mild COVID-19 could contribute to protection against re-infection.

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Targeted reconstruction of T cell receptor sequence from single cell RNA-sequencing links CDR3 length to T cell differentiation state

10.1101/072744 ◽

2016 ◽

Cited By ~ 4

Author(s):

Shaked Afik ◽

Kathleen B. Yates ◽

Kevin Bi ◽

Samuel Darko ◽

Jernej Godec ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Single Cell ◽

Rna Sequencing ◽

Cell Response ◽

T Cell Response ◽

Effector Memory ◽

Cell State ◽

Tcr Repertoire ◽

Single Cell Rna Sequencing

ABSTRACTThe T cell compartment must contain diversity in both TCR repertoire and cell state to provide effective immunity against pathogens1,2. However, it remains unclear how differences in the TCR contribute to heterogeneity in T cell state at the single cell level because most analysis of the TCR repertoire has, to date, aggregated information from populations of cells. Single cell RNA-sequencing (scRNA-seq) can allow simultaneous measurement of TCR sequence and global transcriptional profile from single cells. However, current protocols to directly sequence the TCR require the use of long sequencing reads, increasing the cost and decreasing the number of cells that can be feasibly analyzed. Here we present a tool that can efficiently extract TCR sequence information from standard, short-read scRNA-seq libraries of T cells: TCR Reconstruction Algorithm for Paired-End Single cell (TRAPeS). We apply it to investigate heterogeneity in the CD8+T cell response in humans and mice, and show that it is accurate and more sensitive than previous approaches3,4. We applied TRAPeS to single cell RNA-seq of CD8+T cells specific for a single epitope from Yellow Fever Virus5. We show that the recently-described "naive-like" memory population of YFV-specific CD8+T cells have significantly longer CDR3 regions and greater divergence from germline sequence than do effector-memory phenotype CD8+T cells specific for YFV. This suggests that TCR usage contributes to heterogeneity in the differentiation state of the CD8+T cell response to YFV. TRAPeS is publicly available, and can be readily used to investigate the relationship between the TCR repertoire and cellular phenotype.

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Targeting Myeloma-Associated Macrophage Inhibits Multiple Myeloma Progression By Enhancing Anti-Tumor Cytotoxic CD4+ T Cell Response

Blood ◽

10.1182/blood.v128.22.481.481 ◽

2016 ◽

Vol 128 (22) ◽

pp. 481-481

Author(s):

Wang Qiang ◽

Yong Lu ◽

Rong Li ◽

Zhen Cai ◽

Jian Hou ◽

...

Keyword(s):

Flow Cytometry ◽

T Cell ◽

Cell Response ◽

Myeloma Cell ◽

T Cell Response ◽

Cd4 T Cell ◽

Antibody Treatment ◽

Stimulating Factor

Abstract Background: Multiple myeloma (MM) is an incurable plasma cell cancer characterized by tumor cell accumulation and expansion in the bone marrow (BM). One of the major problems is that MM BM microenvironment is a tumor promoting and immune suppressive milieu. We previously discovered that macrophages (MФs), in particular myeloma-associated MФs (mMФs), heavily infiltrated into MM BM and mediated chemoresistance in MM. Colony-stimulating factor 1 receptor (CSF1R), also known as macrophage colony-stimulating factor receptor (M-CSFR), plays an important role as regulator of the development, morphology, survival, and functions of tissue macrophages as well as tumor-associated macrophages (TAMs). CSF1R blockade by inhibitors and antibodies has been shown promising to treat different tumors, such as glioma, pancreatic cancer, and diffuse-type giant cell tumor. We here assessed the impact of CSF1R blockade by CSF1R antibodies from Imclone (Lilly) on human and murine mMФs, MM growth in vivo, and anti-myeloma immune response in the BM microenvironment as well as chemotherapy in MM. Methods: MФ infiltration was determined in the bone marrow (BM) patients with MGUS (n=6), MM (n=6), and compared to healthy donors (HD, n=6). CSF1R signaling blockade was assessed in the monocytes differentiation with M-CSF in the presence of CSF1R antibody or IgG control. CSF1R antibody impact on MФs growth/viability/proliferation was measured by trypan blue exclusion analysis, MTS, and Ki67 flow cytometry analysis. Tumor burden of 5TGM-1-bearing mice with CSF1R blockade treatment was determined by in vivo bioluminescent imaging, ELISA of IgG2b in mouse serum, and flow cytometry analysis of CD138+ myeloma cell infiltration in mouse BM. The effect of CSF1R antibody treatment on mMФ depletion and M1/M2 polarization was determined by flow cytometry and real-time PCR. Impact of CSF1R antibody treatment on cytotoxic CD8+ and CD4+ T cell immune response was measured by intracellular granzyme B flow cytometry and granzyme B ELISPOT. Effector cell-mediated MM cytotoxicity in the presence of mMФs with or without CSF1R treatment was measured by CD138/Annexin V flow cytometry. Survival rate of MM-bearing mice with CSF1R antibody and chemotherapy was evaluated using Kaplan-Meier estimates and log-rank tests using GraphPad Prism 5 software. Results: MΦ accumulation in BM was associated with myeloma development. Blocking CSF1R by humanized and murine CSF1R monoclonal antibodies (CS4 and CS7) not only inhibited monocyte survival and differentiation but also suppressed human and mouse mMΦ survival and development in vitro. Further, Targeting of MФs by either CS7 antibody or DT-mediated MФ killing in LysmCre X Csf1rLsL-DTR C57BL/6 mouse had marked inhibitory effects on established myeloma progression. CSF1R blockade by CS7 treatment reprogrammed the tumor microenvironment toward to an anti-tumor phenotype. CSF1R antibody treatment reduced myeloma cell load in mouse BM, however the anti-MM activity by CSF1R antibody was abolished in immunodeficient Rag-/- mice. Strikingly we found CSF1R blockade mediated anti-MM effect mainly based on CD4+ T cell response by CD8 and CD4 neutralizing antibody. Correspondingly cytotoxic anti-MM CD4+ T cell response enhanced by CSF1R antibody treatment was confirmed by ex vivo ELISPOT and in vitro cytotoxicity assay. Additionally, CSF1R antibody treatment promoted MM drug sensitivity. Conclusion: Our data demonstrated thatMФs play an important role in MM growth and development. Targeting mMФs by CSF1R blockade achieves anti-MM activity by enhancing cytotoxic CD4+ T cell response and promotes chemotherapy on MM, therefore suggesting therapeutic strategies based on interfering with myeloma-macrophage interactions. Disclosures No relevant conflicts of interest to declare.

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