Antigen presenting cell (APC)-targeted hCGβ vaccine for cancer therapy

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3013-3013
Author(s):  
M. Morse ◽  
R. Chapman ◽  
T. Clay ◽  
T. Osada ◽  
A. Hobeika ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Human Monoclonal Antibody ◽  
Injection Site Reaction ◽  
Clinical Activity ◽  
Systemic Delivery ◽  
Gm Csf ◽  
Epithelial Tumors ◽  
Mixed Response ◽  
Vaccine Approach

3013 Background: CDX-1307 is a novel vaccine approach designed to target antigens directly into the endocytic compartments of dendritic cells (DCs) and other professional APCs. The β subunit of human chorionic gonadotropin (hCGβ) is selectively over-expressed by a number of epithelial tumors and has been reported to correlate with stage of disease and prognosis. We have coupled this tumor-associated antigen to a human monoclonal antibody (B11) that targets mannose receptors on human dendritic cells and macrophages, and have demonstrated the efficacy of this approach in preclinical models using hCGβ-expressing tumors and cell lines. Methods: In this phase I, dose-escalating study, sequential cohorts of 6 patients with relapsed epithelial tumors receive 4 biweekly intradermal injections of CDX-1307 at either 0.3, 1.0 or 2.5 mg, or 2.5 mg concurrent with GM-CSF. Objectives: safety and tolerability; DLT, humoral and cellular immune response, and clinical activity. Results: Enrollment in the first three cohorts (n=18) is complete with no DLTs. Common potential treatment-related toxicities were injection site reaction (n=5) and fatigue/malaise (n=4), and were generally mild to moderate in severity. One transient Grade 3 generalized allergic reaction in the 1.0 mg cohort was suspected possibly related to either a nut allergy or CDX-1307. One mixed response was seen, with variable effects on circulating hCGβ. CDX-1307 localized to dermal macrophages and DCs in post-treatment biopsies. Conclusions: Administration of CDX-1307 is well tolerated and results in antigen localization in APCs of the skin. Immune Response and tumor impact are under evaluation. Further development includes systemic delivery that may provide antigen targeting to a broad APC population, and combination with immunostimulants to generate optimal immune responses. No significant financial relationships to disclose.

Use of Dendritic Cells and GM-CSF Adjuvant Are Associated with Anti-Idiotype Cellular Immune Response Following Idiotype Vaccination in Follicular Lymphoma Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 771-771
Author(s):  
Wen-Kai Weng ◽  
Debra Czerwinski ◽  
Ronald Levy
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Follicular Lymphoma ◽  
Molecular Cloning ◽  
Induction Chemotherapy ◽  
Predictive Factor ◽  
Medical Center ◽  
Production Method ◽  
Gm Csf ◽  
Id Protein

Abstract Vaccination with idiotype (Id) induces humoral and/or cellular anti-Id immune responses (IR). Recently, we found that anti-Id humoral IR and IgG Fc receptor FcγRIIIa (CD16) 158 Valine/Valine (V/V) correlated with better outcome in patients receiving Id vaccination (JCO 22:4717). Therefore, identifying factors that influence the development of anti-Id IR will provide important information on how to improve Id vaccination by aiming to increase IR. We examined the following factors for their possible effects on IR: prior induction chometherapy or not, prior fludarabine, clinical response to induction chemotherapy, the production method for Id protein, the immunologic adjuvants used during vaccination and the FcγR polymorphisms. One hundred and eighty follicular lymphoma patients who were treated with Id vaccination at Stanford Medical Center between 1988 and 2002 were included. One hundred and sixty four of them received induction chemotherapy, followed by Id vaccination, while 16 patients were treatment naive at the time of Id vaccination. Humoral and cellular IR were determined following Id vaccination by enzyme-linked immunosorbent assays and by T-cell proliferation assays, respectively, as described. Of these 180 patients, 65 (36%) developed humoral IR and 44 (24%) developed cellular IR after Id vaccination. The development of humoral IR was not affected by receiving induction chemotherapy or not, use of fludrarbine, responses to induction chemtherapy, Id protein production method, type of immunologic adjuvant, FcγRIIIa, FcγRIIa or FcγRIIb genotypes. On the other hand, the development of cellular IR was greatly enhanced by using either dendritic cells or GM-CSF as adjuvant compared to chemical adjuvant (chemical adjuvant: 12% vs dendritic cells: 34%, p=0.003; vs GM-CSF: 48%, p<0.0001) and in patients who received Id protein from molecular cloning (hybridoma: 17% vs molecular cloning: 44%, p=0.0004). However, there was no impact on cellular IR by: induction chemotherapy (23% vs 44%, p=0.072), use of fludrarbine (20% vs 24%, p=0.821), induction chemtherapy responses (CR/CRu: 25% vs PR: 18%, p=0.415), FcγRIIIa genotype (V/V: 27% vs F carrier: 16%, p=0.806), FcγRIIa genotype (H/H: 34% vs R carrier: 23%, p=0.316) and FcγRIIb genotype (I/I: 21% vs T carrier: 37%, p=0.061). A logistic regression analysis was performed to identify independent prognostic variables influencing the development of either humoral or cellular IR. Use of dendritic cells or GM-CSF adjuvant emerged as the only predictive factor independently predicting the development of cellular IR (odds ratio: 4.72, 95% CI: 1.88–11.85, p=0.001), while no predictive factor was identified for the development of humoral IR. This observation is consistent with the prevailing notion that dendritic cells and GM-CSF adjuvant can facilitate cellular IR immune response to various vaccines. It is interesting that PR patients after induction chemotherapy and fludarabine-treated patients had the same chance of developing humoral or cellular IR as did other patients. Therefore, these two groups of patients should not be excluded from subsequent vaccine trials on the assumption that they have impaired immune systems. It is also important to point out that none of these 180 patients received rituximab during induction therapy, which may significantly impair the ability to develop humoral IR.

Adenovirus-Interferon-g (TG1042) Demonstates Clinical Activity in Relapsing Primary Cutaneous Lymphoma (PCL): A Phase I/II Multicentric Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1497-1497
Author(s):  
Mirjana Urosevic ◽  
Thomas E. Luger ◽  
Wolfram Sterry ◽  
Brigitte Dreno ◽  
Olivier Dereure ◽  
...  
Keyword(s):  
Phase I ◽  
Recombinant Adenovirus ◽  
Injection Site Reaction ◽  
Cutaneous Lymphoma ◽  
Clinical Activity ◽  
Severe Toxicity ◽  
Systemic Delivery ◽  
Cdna Insert ◽  
Ifn Γ ◽  
Primary Cutaneous Lymphoma

Abstract PCL has been successfully treated with interferons (IFNs), which can offset the Th2 dominance associated with PCL. Intratumoral (IT) injection of TG1042 (a non-replicating recombinant adenovirus with a human IFN-γ cDNA insert) allows high local levels of IFN-γ without severe toxicity induced by systemic delivery. We undertook a multicentric, phase I/II, open-label, trial of repeated, IT injection of TG1042 in patients with advanced primary T cell (CTCL) and multilesional B cell (CBCL) cutaneous lymphoma. The designated lesions were injected on day 1, 8 and 15 with no injection in the fourth week (1 cycle) and thereafter up to 4 cycles. Immunohistochemistry and qPCR were performed on injected lesions biopsied at baseline and after each cycle. In the phase I step, undertaken on a monocentric basis, 9 patients were enrolled in 3 successive cohorts at the doses of 3×109 viral particles (vp), 3×1010 and 3×1011 vp injected in only one lesion and 9 additonal patients were treated at the doses of 3×1011 vp divided in up to 3 lesions. In the phase II step, 18 additional patients have been planned to be treated on a multicentric basis at 3×1011 vp injected in up to 3 lesions. To date, the 36 planned patients (30 CTCL and 6 CBCL) have been enrolled and received a total of 280 injections, 26 patients have completed the treatment. Treatment is well tolerated with only 3 grade III toxicity. Injection site reaction and flue like syndrom are the most commonly observed adverse events. Local clinical response has been observed in 13 (7 complete responses) out of 27 evaluable patients. Disappearance of non-injected lesions was also observed and led to 12 overall responses (6 complete responses) out of 26 evaluable patients. Histology demonstrates pronounced differences in infiltrate patterns following treatment, with signs of vasculitis and increased numbers of eosinophils, neutrophils, CD8 and TIA-1+ve cells. CD4/CD8 ratio decreased in most tumors. Transgene-IFN-γ mRNA was detectable in injected lesions. Gene expression analysis of biopsies and PBMC shows up-regulation of IFN-γ and various immune response-associated genes. Final clinical and immunological data will be presented. In conclusion, these data show that the administration of TG1042 is well tolerated and results in clinical responses associated with in situ immunological changes. These encouraging results demonstrate a potential significant benefit of TG1042 for the treatment of primary cutaneous lymphoma.

scholarly journals Regulatory impairment in untreated Parkinson’s disease is not restricted to Tregs: other regulatory populations are also involved

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Diana D. Álvarez-Luquín ◽  
Asiel Arce-Sillas ◽  
Jaquelín Leyva-Hernández ◽  
Edgar Sevilla-Reyes ◽  
Marie Catherine Boll ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Immune Response ◽  
Parkinson's Disease ◽  
Dendritic Cells ◽  
Inflammatory Response ◽  
Inflammatory Cells ◽  
Gm Csf ◽  
Tolerogenic Dendritic Cells ◽  
Tnf Α ◽  
Cell Subpopulations

Abstract Background Parkinson’s disease (PD) is the second most common neurodegenerative disease in the world. Various studies have suggested that the immune response plays a key role in this pathology. While a predominantly pro-inflammatory peripheral immune response has been reported in treated and untreated PD patients, the study of the role of the regulatory immune response has been restricted to regulatory T cells. Other immune suppressive populations have been described recently, but their role in PD is still unknown. This study was designed to analyze the pro and anti-inflammatory immune response in untreated PD patients, with emphasis on the regulatory response. Methods Thirty-two PD untreated patients and 20 healthy individuals were included in this study. Peripheral regulatory cells (CD4+Tregs, Bregs, CD8+Tregs, and tolerogenic dendritic cells), pro-inflammatory cells (Th1, Th2, and Th17 cells; active dendritic cells), and classical, intermediate, and non-classical monocytes were characterized by flow cytometry. Plasmatic levels of TNF-α, IFN-γ, IL-6, GM-CSF, IL-12p70, IL-4, IL-13, IL-17α, IL-1β, IL-10, TGF-β, and IL-35 were determined by ELISA. Results Decreased levels of suppressor Tregs, active Tregs, Tr1 cells, IL-10-producer CD8regs, and tolerogenic PD-L1+ dendritic cells were observed. With respect to the pro-inflammatory response, a decrease in IL-17-α and an increase in IL-13 levels were observed. Conclusion A decrease in the levels of regulatory cell subpopulations in untreated PD patients is reported for the first time in this work. These results suggest that PD patients may exhibit a deficient suppression of the pro-inflammatory response, which could contribute to the pathophysiology of the disease.

scholarly journals Opposing effects of dehydroepiandrosterone and dexamethasone on the generation of monocyte-derived dendritic cells

2000 ◽  
pp. 687-695 ◽  
Author(s):  
MO Canning ◽  
K Grotenhuis ◽  
HJ de Wit ◽  
HA Drexhage
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
T Cell ◽  
Adrenal Steroid ◽  
Gm Csf ◽  
Functional Capabilities ◽  
T Cell Stimulation ◽  
Continuous Presence ◽  
High Level ◽  
Opposing Effects

BACKGROUND: Dehydroepiandrosterone (DHEA) has been suggested as an immunostimulating steroid hormone, of which the effects on the development of dendritic cells (DC) are unknown. The effects of DHEA often oppose those of the other adrenal glucocorticoid, cortisol. Glucocorticoids (GC) are known to suppress the immune response at different levels and have recently been shown to modulate the development of DC, thereby influencing the initiation of the immune response. Variations in the duration of exposure to, and doses of, GC (particularly dexamethasone (DEX)) however, have resulted in conflicting effects on DC development. AIM: In this study, we describe the effects of a continuous high level of exposure to the adrenal steroid DHEA (10 M) on the generation of immature DC from monocytes, as well as the effects of the opposing steroid DEX on this development. RESULTS: The continuous presence of DHEA (10 M) in GM-CSF/IL-4-induced monocyte-derived DC cultures resulted in immature DC with a morphology and functional capabilities similar to those of typical immature DC (T cell stimulation, IL-12/IL-10 production), but with a slightly altered phenotype of increased CD80 and decreased CD43 expression (markers of maturity). The continuous presence of DEX at a concentration of 10 M in the monocyte/DC cultures resulted in the generation of plastic-adherent macrophage-like cells in place of typical immature DC, with increased CD14 expression, but decreased expression of the typical DC markers CD1a, CD40 and CD80. These cells were strongly reactive to acid phosphatase, but equally capable of stimulating T cell proliferation as immature DC. The production of IL-12 by these macrophage-like cells was virtually shut down, whereas the production of IL-10 was significantly higher than that of control immature DC. CONCLUSION: The continuous presence of a high level of GC during the generation of immature DC from monocytes can modulate this development away from DC towards a macrophage-like cell. The combination of a low CD80 expression and a shutdown of IL-12 production suggests the possibility of DEX-generated cells initiating a Th2-biased response. These effects by DEX on DC development contrast with those by DHEA, which resulted in a more typical DC although possessing a phenotype possibly indicating a more mature state of the cell.

scholarly journals MicroRNA Profiling of Activated and Tolerogenic Human Dendritic Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Zuzana Stumpfova ◽  
Renata Hezova ◽  
Albano Carlo Meli ◽  
Ondrej Slaby ◽  
Jaroslav Michalek
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Dendritic Cells ◽  
Gene Expression Regulation ◽  
Surface Markers ◽  
Gm Csf ◽  
Microrna Profiling ◽  
Tolerogenic Dendritic Cells ◽  
Mirnas Expression ◽  
Human Dendritic Cells

Dendritic cells (DCs) belong to the immune system and are particularly studied for their potential to direct either an activated or tolerogenic immune response. The roles of microRNAs (miRNAs) in posttranscriptional gene expression regulation are being increasingly investigated. This study’s aim is to evaluate the miRNAs’ expression changes in prepared human immature (iDCs), activated (aDCs), and tolerogenic dendritic cells (tDCs). The dendritic cells were prepared using GM-CSF and IL-4 (iDC) and subsequently maturated by adding LPS and IFN-γ(aDC) or IL-10 and TGF-β(tDC). Surface markers, cytokine profiles, and miRNA profiles were evaluated in iDC, tDC, and aDC at 6 h and 24 h of maturation. We identified 4 miRNAs (miR-7, miR-9, miR-155 and miR-182), which were consistently overexpressed in aDC after 6 h and 24 h of maturation and 3 miRNAs (miR-17, miR-133b, and miR-203) and miR-23b cluster solely expressed in tDC. We found 5 miRNAs (miR-10a, miR-203, miR-210, miR-30a, and miR-449b) upregulated and 3 miRNAs downregulated (miR-134, miR-145, and miR-149) in both tDC and aDC. These results indicate that miRNAs are specifically modulated in human DC types. This work may contribute to identifying specific modulating miRNAs for aDC and tDC, which could in the future serve as therapeutic targets in the treatment of cancer and autoimmune diseases.

Anti-Myeloma Effects Induced by Myeloma Idiotype Pulsed Dendritic Cells In Vitro.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5131-5131
Author(s):  
Mei Zhang ◽  
Xiaoran Yin ◽  
Yunya Luo ◽  
Xiu Lin ◽  
Pengcheng He ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Peripheral Blood ◽  
Gm Csf ◽  
Tnf Α

Abstract As the most potent antigen-presenting cells, Dendritic cells (DCs), capable of inducing immune responses from naive T cells, are operative tools for tumor immunotherapy. Derived DCs are extremely effective in capturing and presentation of antigens to T cells and play a key role in the induction of cytotoxic T lymphocytes (CTLs). In vitro culture system containing the combination of GM-CSF, IL-4 and TNF-α cytokine can affect CD14 + progenitor cells from mononuclear cells (MNCs) of peripheral blood (PB) developing into functional DCs, which have enough quantities for application in vitro researches and clinical practices. Multiple myeloma cells(MM)are able to secrete a great quantity of immunoglobulin (Ig) expressing idiotypic antigen called idiotype (Id) in its mutational hotspot. This kind of idiotypic structure regions also expressing on the surface of MM cells are high specific autologous tumor associated antigen (TAA). The combination use of DCs and tumor specific antigen can improve the immunogenicity of MM cells and stimulate specific anti-tumor immunological response effectively, so by using this new kind of DC tumor vaccine, following high dose chemical therapy, the tiny residual pathological changes might be cleared totally in the future. To investigate the specific antitumor immune response induced by Id-pulsed dendritic cells(DCs) in vitro. DCs were generated from peripheral blood monocytes of the multiple myeloma(MM) patients using GM-CSF, IL-4, and TNF-α. pulsed with idiotype protein at the immature stage, DCs could activate T cells to become tumor specific cytotoxic T lymphocytes (CTLs). The morphologic characteristics of those cells were observed with light and electron microscopes. The phenotypic figures were analyzed with FACS analysis. Methy-thiazoly-Tetrazolium (MTT) assay was employed to evaluate the effect of proliferation of autologous T cells and the inhibition rate of CTL on MM cells. DCs precursors in peripheral blood could be induced to typical mature DCs in medium containing GM-CSF, IL-4 and TNF-α. Mature DCs with Id could operatively increase proliferation of the autologous T cells and active naive T cells to become tumor specialized CTLs. Any doses of CTLs had significant inhibition or killing ability on autologous MM cells. These results suggest in suitable cytokine environment, the precursors in peripheral blood of MM patients could be induced to functional DCs, and vaccination with Id-pulsed DCs could induce active antitumor immune response. Multiple cycles of immunization using DC as APC in vitro can be beneficial in generating antigen- specific T cells from normal PBMC, and Id an auto-specific tumor antigen, can be got with ammonium sulfate four-step precipitated method, By digestion of pepsin and affinity chromatography so as to stimulate MM specific immunological responce, and Id-pulsed mature DCs from MM patients can stimulate not only the proliferation of autologous T cells, but also the specific CTL immune response against autologous MM cells. In addition, in vitro immunization may provide an alternative approach to in vivo immunization of MM. We believe that DCs vaccine can bring the breakthrough of therapy to MM in the near future.

Vaccination with Dendritic Cells Loaded with Autologous Leukemic Cells in Combination with Low-Dose Lenalidomide Induced Immune Responses in Chronic Lymphocytic Leukemia (CLL) Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4685-4685
Author(s):  
Lotta Hansson ◽  
Marzia Palma ◽  
Lars Adamson ◽  
Harriet Ryblom ◽  
Barbro Näsman-Glaser ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Dendritic Cells ◽  
Immune Responses ◽  
Lymphocyte Count ◽  
Low Dose ◽  
Autologous Tumor ◽  
Proliferation Assay ◽  
Tumor Vaccination ◽  
Gm Csf

Abstract Background and aim. We have previously demonstrated that immunization with ex-vivo generated autologous dendritic cells loaded with apoptotic tumor cells (Apo-DC) induces specific immune responses in CLL patients especially when combined with GM-CSF and low-dose cyclophosphamide (CTX) (Palma et al, CII 2012). In this study we evaluate the safety and immunogenicity of Apo-DC vaccination in combination with low-dose lenalidomide alone, or in combination with GM-CSF and low-dose CTX in CLL patients. In patients with multiple myeloma, lenalidomide boosted the response to a pneumococcal vaccine (Noonan et al, Clin Ca Res 2012); lenalidomide may thus be a useful adjuvant also with tumor vaccines but has not yet been explored in man. In patients with CLL, lenalidomide has immunomodulatory properties including NK and T cell stimulation, as well as enhanced immunoglobulin production. Lenalidomide also induced a clinical "flare" reaction, upregulated adhesion molecules and facilitated synapse formation between CLL and T cells (Ramsay et al, J Clin Invest 2008; Shanafelt et al, Blood 2013)i.e. effects of advantage in tumor vaccination. We here report on the first results using lenalidomide as an adjuvant in tumor vaccination in man. Methods. Ten patients with slowly progressive but asymptomatic CLL were included. The first five patients were immunized intradermally five times during fourteen weeks with a mean of 16x106 Apo-DCs. Low-dose lenalidomide was given daily as an adjuvant at a dose of 2.5 mg from start of vaccination, for four weeks, and then escalated to 5 mg daily until week 24 (cohort I). The next five patients were treated in the same way but also received 300 mg/m2 CTX at day -3 and GM-CSF sc day 1-4 (cohort II). Clinical and immune effects of the vaccination were evaluated at regular time intervals for 1 year. A vaccine-induced immune response was defined as a ≥ 2-fold increase compared to pre-immunization values in either 3H-thymidine incorporation (proliferation) assay or ELISpot assay as described (Palma et al, CII 2012). Changes in the numbers of lymphocyte subpopulations including regulatory T cells (Tregs) as well as in T-cells expressing activation (CD69, CD137) and regulatory markers (CD103) were also evaluated. Results. To date, the 8 first included patients have completed treatment as planned and passed study week 52. The remaining 2 patients are between study week 24 and 52. No adverse events (AE) > grade 2 have been observed with the exception of one patient who had grade 3 hemolysis (AIHA) at study week 6 (cohort I) and one patient who had grade 4 thrombocytopenia at study week 5 (cohort II). AIHA was treated with steroids and lenalidomide was temporarily withdrawn for 4 weeks. The grade 4 thrombocytopenia required a 10 weeks withdraw of lenalidomide, upon which the thrombocytopenia resolved to grade 1. A decrease in the lymphocyte count fulfilling the criteria for partial response (clinical PR) was seen in 5 patients during lenalidomide treatment (one in cohort I and four in cohort II), but the lymphocyte count increased again to pre-vaccination levels at withdrawal of lenalidomide at week 24. Vaccine-induced immune responses were noted in 4/5 patients in cohort I and in 2/5 patients in cohort II. An inverse correlation between Tregs numbers and proliferation assay values was observed (r = -0.46, p=0.0015) i.e. high proliferative response was associated with low Tregs count. Changes in T cells expressing activation markers (CD69 and CD137) as well as the regulatory marker CD103 were also observed. Summary/conclusions. This is the first study on lenalidomide as an immunomodulatory agent in tumor vaccination. The results indicate that immunization of CLL patients with autologous tumor-loaded DCs combined with low-dose lenalidomide induced specific immune responses in CLL patients. Lenalidomide as a low-dose immune adjuvance had acceptable tolerability. This therapeutic approach should be explored further to define an optimal combination of vaccination schedule, lenalidomide dose and combination with other immunomodulatory agents interfering with the tumor-microenvironment with the aim to induce a potent immune response with a clinical impact. Disclosures Off Label Use: Lenalidomide is used as an adjuvant in this CLL vaccination study. Österborg:Celgene: DMC memeber of Celgene-initiated phase 3 trials Other.

Breast cancer: Draining lymph node of vaccination site targeted by adjuvant GM-CSF in an autologous vaccine

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 13506-13506
Author(s):  
E. Garcia-Giralt ◽  
E. Lasalvia-Prisco ◽  
S. Cucchi ◽  
M. Aghazarian ◽  
J. Larrañaga ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Systemic Immune Response ◽  
Vaccination Site ◽  
Gm Csf ◽  
Draining Lymph Node

13506 Background: We have reported the sensitization against Tumor Associated Antigens (TAA) and the tumor antiprogressive effect of Autologous Thermostable Hemoderivative-Cancer Vaccine (ATH-CV) in breast cancer patients (E. Garcia-Giralt et al ASCO, 2006). Systemic immune response elicited by TAA is started by a locoregional immune response at the microenvironment constituted by the antigens source and the draining lymph node. The antigens source can be a tumor or a vaccination site and respectively, the draining lymph node is the sentinel lymph node (SLN) or the Sentinel Immunized Node (SIN). Tolerogenic or protective locoregional immune response is decisional because it starts a corresponding systemic immune response, tolerogenic or protective. GM-CSF is a conditioner of SLN and SIN, switching the locoregional immune responses from tolerogenic to protective (ML Disis et al Blood, 1996; AJ Cochran et al Nat Rev Immunology, 2006). Therefore, to optimize the ATH-CV antitumoral effect, we have explored GM-CSF as a locoregional adjuvant. Methods: Thirty six M1 breast cancer patients, ER+,HER 2-, hormone and chemotherapy resistant, performance status = 2, and CA 15–3 rising level, were included in this prospective, IRB-approved phase I/II trial. Patients were 3-group (G) randomized (12 each), submitted to different treatments: G1, no additional oncology treatment; G2, ATH-CV; G3, ATH-CV plus GM-CSF at vaccination site 150 μg/day, 5 days. Statistic assessment (Student’s t-test) was performed at the 30-day end point: ATH sensitization by Delayed Type Hypersensibility test (DTH) and Lymphocyte Proliferative Assay (LPA); PSA serum level and immunophenotyping of lymph node cells in biopsies of SIN scintigraphy-localized. Results: Significant differences (p<0.05): DTH test > 5 mm: G1, 0/12; G2, 3/12 and G3, 6/12. LPA > 2.0: G1, 0/12; G2, 4/12 and G3, 7/12. Immunophenotyping: MHC-II+CD83+ (Mature Dendritic Cells):G3>G2>G1. 30 days CA 15–3 increase: G1>G2>G3. No relevant toxicities were evidenced. Conclusions: In advanced breast cancer, ATH-CV sensitization and tumor antiprogressive effect were potentiated by GM-CSF as local adjuvant. Increase of SIN mature dendritic cells is suggested as mechanism of action. No significant financial relationships to disclose.

A phase I, open-label, dose-escalation and cohort expansion study evaluating the safety and immune response to autologous dendritic cells transduced with AdGMCA9 in patients with metastatic renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 653-653
Author(s):  
Izak Faiena ◽  
Nazy Zomorodian ◽  
Begonya Comin-Anduix ◽  
Ankush Sachadeva ◽  
Adrian Bot ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Dose Escalation ◽  
Mononuclear Cells ◽  
Clear Cell ◽  
Fusion Gene ◽  
Recombinant Adenovirus ◽  
Antitumor Effects ◽  
Gm Csf

653 Background: We developed a fusion gene construct, GM-CSF + CAIX, transduced by a replication deficient adenovirus into autologous dendritic cells (DC) that are injected in patients with metastatic RCC (mRCC) in this phase 1 study targeting CAIX overexpressed on RCC tumors. Methods: A recombinant adenovirus encoding the GMCSF-CAIX fusion gene (AdGMCAIX) manufactured per GMP in collaboration with the NCI Rapid Access to Intervention Development (RAID) program. The final product was produced using DCs produced ex-vivo from patients’ peripheral blood mononuclear cells (PBMC), by culturing with GM-CSF & IL-4, then engineered with AdGMCAIX prior to intradermal injection. The injected transduced DCs were expected to stimulate an antigen specific immune response against CAIX expressing RCC. Three dose escalation cohorts (5, 15, and 50 X 106 cells/administration) were injected based on 3+3 design. DC-AdGMCAIX was given intradermally q2wkX3 doses. The primary aim is safety. Secondary aims are to evaluate immune responses & antitumor effects per RECIST 1.1. Eligibility criteria included patients with clear cell mRCC with ECOG 0-1, measurable disease, and adequate organ function. Results: Fifteen patients with clear cell mRCC were enrolled. Nine patients received all 3 planned vaccine doses, comprising DC expressing CAIX, CD11c and other relevant markers. No serious adverse events (SAEs) were seen. Grade 1/2 AEs include fatigue (3/1), leukopenia (1/1) and flu-like symptoms (0/1). Of the 9 patients who received treatment, 1 expired of progressive disease (PD), 2 patients were lost to follow-up and 6 patients are alive. Of the 6 patients, 5 have PD and are currently receiving standard-of-care therapies, and 1 has completed treatment with stable disease at 6 mon follow up and is being evaluated for retreatment. Conclusions: These early data show that autologous DC transduced by Ad-GMCAIX vector can be safely given to mRCC patients without any SAEs noted at the doses tested. These data support further development of Ad-GMCAIX vaccine strategies, either alone, or in combination with approved therapies. Clinical trial information: NCT01826877.

Cytokine regulation of the macrophage (M phi) system studied using the colony stimulating factor-1-deficient op/op mouse

1996 ◽  
Vol 76 (4) ◽  
pp. 927-947 ◽  
Author(s):  
W. Wiktor-Jedrzejczak ◽  
S. Gordon
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
Dendritic Cells ◽  
Growth Factors ◽  
Colony Stimulating Factor ◽  
Gm Csf ◽  
Local Populations ◽  
Tissue Reactions ◽  
Stimulating Factor

The macrophage (M phi) lineage is more complex than other myeloid lineages of hematopoietic cells and includes strikingly different end cells such as Kupffer cells, alveolar M phi, histiocytes, serosal M phi, synovial type A cells, microglia, osteoclasts, and possibly dendritic cells. These cells are formed under the influence of primary M phi growth factors such as colony stimulating factor (CSF)-1, granulocyte-M phi (GM)-CSF, and interleukin-3. The dissection of the system has been greatly facilitated by discovery of the osteopetrotic op/op mouse, which has a spontaneous knockout of the gene for CSF-1 and possesses generalized but differential deficiency of various local subpopulations of M phi. Studies using this model indicate that the M phi lineage is split into CSF-1-dependent and CSF-1-independent cells that are largely independently regulated. These contribute variably to different local populations and have largely, but not totally, overlapping functions. Both CSF-1 and GM-CSF are responsible for transition of cells of the M phi lineage from bone marrow to blood, and from blood to tissues, and have a critical extramedullary role. Regulation of the M phi system by CSF-1 is complex, with some local populations dependent on circulating CSF-1 and some supported exclusively by locally produced CSF-1. Colony stimulating factor-1-dependent M phi are not required for the generation of a specific immune response. Instead, most likely they play a regulatory role in various tissue reactions including responses to bacterial infection, neoplasia, and atherosclerosis. A hypothetical major role of CSF-1-independent M phi is to collaborate with lymphocytes in mounting an immune response. These issues need further exploration using animals with knockouts of genes for other M phi growth and activation factors and their receptors.

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