Human Autologous Tumor-Specific T-Cell Responses Induced by Liposome Encapsulated Lymphoma Membrane Proteins.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 749-749 ◽  
Author(s):  
Sattva S. Neelapu ◽  
Barry L. Gause ◽  
Linda Harvey ◽  
Andrea R. Frye ◽  
Jessie Horton ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Membrane Proteins ◽  
Tumor Cells ◽  
T Cell Responses ◽  
Phase Iii ◽  
Autologous Tumor ◽  
Vaccine Formulation ◽  
Cell Responses ◽  
Id Protein

Abstract The unique antigenic determinants (Idiotype [Id]) of the immunoglobulin expressed on a given B cell malignancy can serve as a tumor-specific antigen for active immunotherapy. We have previously demonstrated that Id vaccines in follicular lymphoma (FL) patients administered in the minimal residual disease (MRD) state are immunogenic and are associated with induction of complete molecular remissions and long-term disease-free survival (Nature Med 5:1171–1177, 1999). This hybridoma-derived vaccine is now being tested in a pivotal Phase III clinical trial. However, the production of Id protein by hybridoma technology for such vaccine formulation is an expensive and laborious process requiring an average of 3 to 6 months to manufacture the vaccine for each patient. To overcome this difficulty, we developed a novel vaccine formulation where we directly extracted the membrane proteins from lymph node biopsy-derived tumor cells and incorporated them into liposomes along with IL-2. Testing in preclinical studies showed this formulation to be as potent as our prototype hybridoma-derived Id protein vaccine. In the present study, 11 previously untreated and/or relapsed FL patients received 5 injections of this novel vaccine formulation subcutaneously and/or intratumorally at approximately monthly intervals. The vaccine was well tolerated and induced only minor local reactions at the sites of injection. T cell responses were evaluated by cytokine induction and IFNg ELISPOT against autologous tumor. Post-vaccine, but not pre-vaccine, peripheral blood mononuclear cells (PBMC) from 6 out of 10 patients that were assessed, recognized autologous tumor cells, as demonstrated by TNFa, GM-CSF and/or IFNg production. Significant production of cytokines was observed only in response to autologous tumor cells, but not normal B cells. The precursor frequency of tumor-reactive T cells was significantly increased in postvaccine PBMC (range 19–115 IFNg spots/100,000 PBMC), compared with prevaccine PBMC (range 2–7 IFNg spots/100,000 PBMC). Anti-MHC Class I and Class II antibodies inhibited cytokine production suggesting that both CD4+ and CD8+ T cells were involved in the anti-tumor immune responses. Vaccination was associated with induction of a sustained complete response in one patient and correlated with the generation of a potent anti-tumor T cell response. The remaining 10 patients progressed after a median duration of 8 months. We conclude that liposomal delivery of lymphoma membrane proteins is safe, induces tumor-specific CD4+ and CD8+ T cell responses, and may serve as a model for vaccine development against other human cancers. The induction of clinical response warrants further testing of this novel formulation in the setting of MRD where the immunosuppressive effects of the tumor are likely to be least.

Autologous Whole Tumor Cell Vaccination Early After Allogeneic Stem Cell Transplantation Elicits Anti-Tumor T Cell Responses in Patients with Advanced Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1892-1892
Author(s):  
Ute E. Burkhardt ◽  
Ursula Hainz ◽  
Kristen E. Stevenson ◽  
Di Wu ◽  
Vincent T. Ho ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Research Funding ◽  
T Cell Responses ◽  
Lymphocytic Leukemia ◽  
Autologous Tumor ◽  
Post Transplant ◽  
Cell Responses

Abstract Abstract 1892 Patients with advanced hematological malignancies remain at high risk for eventual disease progression following reduced intensity conditioning (RIC) allogeneic hematopoietic stem cell transplantation (allo-HSCT). We hypothesized that vaccination with whole leukemia cells during the critical period of immune reconstitution early after transplant may enhance antitumor immunity and facilitate expansion of leukemia-reactive T cell responses. We tested this hypothesis in a prospective clinical trial, in which patients with advanced chronic lymphocytic leukemia (CLL) received up to 6 vaccine doses initiated between day 30–45 following RIC allo-HSCT. Each vaccine consisted of 1×107 irradiated autologous tumor cells admixed with 1×107 irradiated K562 bystander cells secreting GM-CSF (GM-K562). All patients received tacrolimus and mini-methotrexate as graft-versus-disease (GvHD) prophylaxis. Tacrolimus was maintained at therapeutic levels during the vaccination period without taper. Twenty-two patients were enrolled, all with advanced disease (median number of prior therapies 3; range 2–11). Many of the leukemias expressed markers associated with aggressive disease (e.g. unmutated IgVH - 68%) and displayed high-risk cytogenetic abnormalities (sole del(11q) - 41%; sole del(17p) - 23%; del(11q and 17p) - 18%). Greater than 50% (n=13) of patients had persistent marrow involvement (≥10%) at time of allo-HSCT. Eighteen of 22 subjects were vaccinated after allo-HSCT and received a median of 6 (range 1–6) vaccines. The remaining 4 patients were precluded from vaccination due to development of acute GvHD before day 45. Vaccines were generally well tolerated, but mild, transient injection site erythema was common. Only one grade 4 event (neutropenia) with a possible attribution to treatment occurred. We observed a similar incidence of grade II-IV aGvHD at 1 year in the 18 vaccinated patients (39%; 95% CI: 17–61%) and 42 control CLL patients that underwent RIC allo-HSCT at our institution from 2004–2009 (31%; 95%CI: 18–46%). At a median follow-up of 2.9 (range 1–4) years, the estimated 2-year rates of progression-free survival and overall survival of vaccinated study participants were 80% (95% CI: 54–92%) and 84% (95% CI: 58–95%). With these promising clinical results, we next focused on gaining insight into the mechanism that generated the observed clinical graft-versus-leukemia (GvL) responses. To delineate the specific contribution of vaccination to the overall GvL effect, we performed T cell assays to detect CLL-specific reactivity in serial pre- and post-HSCT samples obtained from vaccinated patients (n=9) who received median of 6 vaccines (range 3–6). In comparison, we examined T cell responses in study subjects (n=4) that developed aGvHD at a median of 44.5 days (range 26–56) after HSCT; and control CLL patients (n=4; no vaccine, no GvHD in the early post-transplant period) that were not enrolled in the study. Although early post-transplant vaccination had no impact on recovering absolute T cell numbers, reactivity of CD8+ T cells from the vaccinated patients was consistently directed against autologous tumor cells but not alloantigen bearing-recipient cells (PHA T cell blasts and fibroblasts) in IFNγ ELISpot assays. A peak response against autologous tumor cells was reached at day 60 after allo-HSCT (average 221 SFC/5×105 cells vs. 29 and 33 average SFC/5×105cells for PHA blasts and fibroblasts, respectively). CD8+ T cell clones were isolated from 4 vaccinated study subjects by limiting dilution and 17% (range 13–33%) reacted solely against CLL-associated antigens. In contrast, broad CD8+ T cell reactivity indicating an alloantigen response was observed in GvHD patients, while no increase in T cell reactivity against tumor-associated or alloantigens was seen in control patients. Tumor-reactive CD8+ T cells isolated from vaccinated patients secreted a broad profile of effector cytokines (GM-CSF, TNFα and IP10). Moreover, the amount of cytokines secreted by these CLL-specific CD8+ T cells steadily increased following early post-transplant vaccination, but not after allo-HSCT alone or in relation to GvHD. Our studies reveal that vaccination with autologous whole CLL/GM-K562 cells between days 30–100 after allo-HSCT is associated with induction of immunity against recipient CLL cells, and suggest that this is an effective strategy for promoting GvL following RIC allo-HSCT. Disclosures: Brown: Genzyme, Celgene: Research Funding; Calistoga, Celgene, Genentech, Pharmacyclics, Novartis, Avila: Consultancy. Cutler:Pfizer, inc: Research Funding; Astellas, Inc: Consultancy, Research Funding.

scholarly journals Profile of a Serial Killer: Cellular and Molecular Approaches to Study Individual Cytotoxic T-Cells following Therapeutic Vaccination

2011 ◽  
Vol 2011 ◽  
pp. 1-21 ◽  
Author(s):  
Emanuela M. Iancu ◽  
Petra Baumgaertner ◽  
Sébastien Wieckowski ◽  
Daniel E. Speiser ◽  
Nathalie Rufer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Biology ◽  
Large Scale ◽  
T Cell Responses ◽  
Serial Killer ◽  
Phase Iii ◽  
Cell Responses ◽  
T Cell Vaccination ◽  
Human T Cell

T-cell vaccination may prevent or treat cancer and infectious diseases, but further progress is required to increase clinical efficacy. Step-by-step improvements of T-cell vaccination in phase I/II clinical studies combined with very detailed analysis of T-cell responses at the single cell level are the strategy of choice for the identification of the most promising vaccine candidates for testing in subsequent large-scale phase III clinical trials. Major aims are to fully identify the most efficient T-cells in anticancer therapy, to characterize their TCRs, and to pinpoint the mechanisms of T-cell recruitment and function in well-defined clinical situations. Here we discuss novel strategies for the assessment of human T-cell responses, revealing in part unprecedented insight into T-cell biology and novel structural principles that govern TCR-pMHC recognition. Together, the described approaches advance our knowledge of T-cell mediated-protection from human diseases.

scholarly journals Heat Shock Treatment of Tumor Lysate-Pulsed Dendritic Cells Enhances Their Capacity to Elicit Antitumor T Cell Responses against Medullary Thyroid Carcinoma

2006 ◽  
Vol 91 (11) ◽  
pp. 4571-4577 ◽  
Author(s):  
Thomas Bachleitner-Hofmann ◽  
Michaela Strohschneider ◽  
Peter Krieger ◽  
Monika Sachet ◽  
Peter Dubsky ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Heat Shock ◽  
Tumor Cells ◽  
T Cell Responses ◽  
Cytotoxic T Cell ◽  
Tumor Lysate ◽  
Cell Responses ◽  
Cytotoxic T Cell Responses

Abstract Background: In vitro and in vivo studies have shown that dendritic cells (DCs) can stimulate antitumor T cell responses against medullary thyroid carcinoma (MTC). However, despite promising results in selected cases, the clinical efficacy of DC immunotherapy in patients with MTC has been limited. Recently, it has been demonstrated in mice that heat shock enhances the capacity of bone-marrow-derived DCs to stimulate antigen-specific T cells. The aim of our investigations was to evaluate whether heat shock also increases the capacity of human monocyte-derived DCs to stimulate antitumor T cell responses against MTC tumor cells. Methods: DCs from six patients with metastatic MTC were pulsed with tumor lysate derived from allogeneic MTC tumor cells and were heat shocked for 12 h at 40 C or kept at 37 C. Thereafter, the DCs were matured and cocultured with T cells. Finally, the cytotoxic activity of T cells against MTC tumor cells was measured in vitro. Results: In all patient samples, cytotoxic T cell responses against MTC tumor cells could be induced. Notably, heat-shocked DCs were more potent stimulators of cytotoxic T cell responses than control DCs, with T cells stimulated with heat-shocked DCs displaying a significantly increased cytotoxic activity against MTC tumor cells as compared with T cells stimulated with control DCs. In none of the experiments was a cytotoxic T cell response against unrelated pancreatic tumor cells (PANC-1) observed, using both control and heat-shocked DCs. Conclusions: Our study shows that heat-shocking DCs may be a valuable strategy to increase the immunostimulatory capacity of DCs used for immunotherapy of MTC.

IMMU-07. REPROGRAMMING OF MICROGLIA/MACROPHAGES IN GLIOBLASTOMA IMPROVES ANTI-TUMOR T CELL RESPONSES

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi93-vi93
Author(s):  
Valentina Fermi ◽  
Rolf Warta ◽  
Christine Jungk ◽  
Philip Dao Trong ◽  
Andreas Unterberg ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Profiles ◽  
T Cell Responses ◽  
Conditioned Media ◽  
Treatment Modalities ◽  
Autologous Tumor ◽  
Cell Responses

Abstract Glioblastoma (GBM) still remains incurable. In search for new treatment modalities immunotherapy might be attractive but highly depends on a sufficient infiltration and function of effector T cells in an immunosuppressive microenvironment. In this study, we analyzed if blocking or reprogramming M2polarized glioma-associated microglia/macrophages (GAMs) could improve spontaneous effector T cell responses and thus enhance the effectiveness of immunotherapy. This was tested by sorting patient-derived CD11b+ cells from GBM tissues and treating these GAMs with small molecule inhibitors (SMI) targeting the colony stimulating factor1 receptor (CSF1R). Especially CD11b+ cells treated with the SMI GW2580 presented with a reduced expression of the M2 marker CD163 (p < 0.01) and an increased expression of HLA-DR (p < 0.05). Conditioned media of SMI-treated GAMs also contained significantly higher levels of nitrite (p < 0.001) and a reduced concentration of the immunosuppressive cytokine IL-6 (p < 0.05). Moreover, gene expression profiles of GW2580-treated GAMs showed a shift from an immunosuppressive towards a pro-inflammatory phenotype. Most importantly, the addition of conditioned media of GW2580-treated GAMs to a co-culture of autologous tumor and T cells significantly reduced the number of live tumor cells as compared to the use of conditioned media of untreated GAMs (p < 0.05). Interestingly, in some cases the ability of T cells to transmigrate through a dense barrier of autologous tumor-derived endothelial cells could also be increased. In summary, we showed that CSF-1R blockade with the SMI GW2580 can reprogram GAM phenotype and thereby improve T cell activation. This strongly suggests further studies on the use of GW2580 in combination with immunotherapeutic approaches for the treatment of GBM.

Support for a Possible "Vaccinal" Effect of Rituximab; Lymphoma Idiotype Specific T-Cell Responses in Follicular Lymphoma Patients Treated with Rituximab.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3424-3424
Author(s):  
Shannon P. Hilchey ◽  
Ollivier Hyrien ◽  
Richard Bankert ◽  
Daniel P. Gold ◽  
Faith Young ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Mechanism Of Action ◽  
Mononuclear Cells ◽  
T Cell Responses ◽  
Independent Experiment ◽  
Cell Responses ◽  
Consistent Increase ◽  
Id Protein

Abstract Rituximab (Rtx) has shown significant therapeutic activity in follicular lymphoma (FL) patients, yet it’s exact mechanism of action has not been fully defined. Although killing of FL cells through complement dependent cytolysis, antibody dependent cellular cytotoxicity or direct induction of apoptosis may contribute to its effectiveness, these mechanisms are unlikely to be the only ones as; the clinical and molecular responses to Rtx may continue for months after the last dose and; the median duration of the second response to Rtx is longer than that of the first, findings that cannot be explained solely by the above mechanisms. Rtx induced FL cell death likely results in the release of tumor antigens in a pro-inflammatory environment which we hypothesize may provoke a cell-mediated lymphoma specific immune response. Indeed, others have suggested that such a “vaccinal” effect may be an additional mechanism of action but to our knowledge there has been no direct evidence to support this in Rtx treated patients. Methods: To provide support for this hypothesis we examined lymphoma idiotype (Id) specific T-cell responses in peripheral blood mononuclear cells (PBMC) from three patients with relapsed FL. PBMC were obtained prior to and 4–6 weeks after the last of 4 weekly doses (375mg/m2 q week) of Rtx. A lymph node biopsy was obtained prior to Rtx to generate the patient’s Id protein. Dendritic cells (DC) were generated from pre-Rtx PBMC and pulsed with; no protein (control); the patient’s Id protein (Id); or an irrelevant (Irr) protein (Id from another patient). For patient 1, pre- and post-Rtx PBMC were stimulated with the DC for 1 week, while for patients 2 and 3, PBMC were stimulated for 1 week then re-stimulated for another week with fresh DC. Effectors were then assayed in triplicate for IFN-γ producing cells by Elispot. A second independent experiment was conducted in patients 2 and 3 (ie. this study describes data from 3 patients, 5 separate experiments). Results: Pre-Rtx: There was no consistent increase in the number of Id specific or Irr protein specific T-cells as compared to that of control T-cells. Post-Rtx: Whereas there was no consistent increase in the number of Irr protein specific T-cells as compared to that of control T-cells, in all three patients (including both replicates for patients 2 and 3) there was a consistent increase in the number of Id specific T-cells as compared to that of control T-cells. When composite data from all three patients were analyzed using a mixed ANOVA, the following p-values were obtained: Comparison Pre-Rtx Post-Rtx Control vs. Id 0.03 0.0003 Id vs. Irr 0.3 0.0005 Control vs. Irr 0.2 0.9 Comparison Pre-Rtx Post-Rtx Control vs. Id 0.03 0.0003 Id vs. Irr 0.3 0.0005 Control vs. Irr 0.2 0.9 Conclusions: These data provide, to our knowledge, the first support for the hypothesis that Rtx treatment results in an increase in Id specific T-cell responses in FL patients. If indeed this is a mechanism of Rtx activity, then clinical strategies to augment this postulated vaccinal effect, such as anti-CTLA-4 antibodies or Id vaccination post Rtx, may further increase the clinical potential of this agent and change the way we develop combination therapies. Further study of immune responses in a larger number of FL patients treated with Rtx is warranted and ongoing.

An anti-CD40 activating antibody induces dendritic cell maturation and promotes autologous anti-tumor T cell responses in an in vitro mixed autologous tumor cell/lymph node cell model

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2537-2537
Author(s):  
T. B. Hunter ◽  
R. P. Gladue ◽  
S. J. Antonia
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Cell Model ◽  
T Cell Responses ◽  
Lymph Node Cell ◽  
Autologous Tumor ◽  
Cell Responses ◽  
Draining Lymph Node ◽  
Antigen Presenting

2537 Background: CD40-mediated interactions play an important role in the response to a variety of diseases, including cancer. Engagement of CD40 on antigen-presenting cells (APC) by CD40L leads to maturation and upregulation of co-stimulatory molecules, B7.1 and B7.2 (CD80 and CD86), which are requisite in the activation of T cells. Clinical trials involving immunologic interventions have shown clinical responses confirming that the immune system can be harnessed for the treatment of cancer. However, the clinical response rate has been low, signifying the need for new immunotherapeutic strategies. To this end, an agonist antibody specific for CD40 has been developed and is being evaluated as a potential anti-cancer agent. Methods: The activation capacity of anti-CD40 antibody CP-870,893 was analyzed by performing flow cytometric analysis of APC maturation markers following incubation of monocyte derived dendritic cells (DC) with the antibody. IL-12 and macrophage inflammatory protein-1α (Mip1 α) secretion were also analyzed. The effect of the antibody on anti-tumor T cell responses was tested in an autologous human model consisting of tumor cells as stimulator cells and tumor-draining lymph node cells as responders from a series of cancer patients. Results: Cultured DC treated with CP-870,893 consistently display a mature phenotype: robust upregulation of CD80, CD83, CD86 and HLA-DR expression, increased Mip1 α secretion, and the loss of antigen presenting capability. IL-12 secretion was not detected. CP-870,893 also promotes the responsiveness of lymph node derived T cells to autologous tumor, indicated by IFNγ and IL-2 ELISpot. Conclusions: These data demonstrate that CP-870,893 binds to and activates DC. A fully autologous mixed lymph node cell/tumor cell model was used to demonstrate that this activation promotes tumor-specific T cell responses. T cells from the tumor draining lymph node are not responsive to autologous tumor cells, however in the presence of CP-870,893 this unresponsiveness is reversed. These data indicate that CP-870,893 warrants further study as an immunotherapeutic agent in the treatment of cancer. No significant financial relationships to disclose.

CT-011, Anti-PD-1 Antibody, Enhances Ex-Vivo T Cell Responses to Autologous Dendritic/Myeloma Fusion Vaccine Developed for the Treatment of Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 781-781 ◽  
Author(s):  
Jacalyn Rosenblatt ◽  
Brett Glotzbecker ◽  
Heidi Mills ◽  
Whitney Keefe ◽  
Kerry Wellenstein ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Mononuclear Cells ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Normal Volunteers ◽  
Cell Responses

Abstract Abstract 781 We have developed a promising cancer vaccine in which autologous tumor cells are fused with dendritic cells (DCs) resulting in the presentation of tumor antigens in the context of DC mediated costimulation. In animal models, vaccination with fusion cells results in eradication of established tumor, and in clinical trials, both immunologic and clinical responses have been observed. However, response to vaccination may be muted by inhibitory pathways that blunt activated T cell responses. The PD-1/PDL-1 pathway is an important element contributing to tumor mediated immune suppression. In infectious disease models, upregulation of T cell expression of PD-1 is associated with an exhausted phenotype facilitating the development of chronic viral infection. In contrast, PD-1 blockade results in the restoration of functionally active T cells and clearance of infection. The PD-1/PDL-1 pathway is also being evaluated a as a central mechanism by which tumors escape host immunity. CT-011, is a humanized anti PD-1 antibody that is currently evaluated in Phase II studies for the treatment of hematological malignancies and solid tumors. In this study, we evaluated expression of PD-1 on T cells derived from patients with advanced hematologic malignancies, and PDL-1 expression on primary myeloma cells, ex-vivo generated dendritic cells, and DC/tumor fusion cells. We evaluated the effect of PD-1 blockade with CT-011 on T cell response to DC/tumor fusion cell stimulation in vitro. Tumor cells were obtained from bone marrow aspirates of patients with multiple myeloma. Nonadherent peripheral blood mononuclear cells obtained from patients with multiple myeloma and normal volunteers were cultured in RPMI supplemented with 10U/ml IL-2, and expression of PD-1 on CD4+ T cells was assessed by flow cytometric analysis . DCs were generated from adherent mononuclear cells cultured with rhIL-4, GM-CSF and TNFα and fused with tumor cells by coculture in 50% solution of polyethylene glycol. T cells were stimulated by DC/tumor fusions in the presence or absence of 5ug/ml CT-011. We demonstrate that PD-1 expression is markedly upregulated on T cells in patients with advanced multiple myeloma. As compared to a control population of normal volunteers in which mean levels of PD-1 expression was 6% (n=7), mean expression in patients with multiple myeloma was 20% (n=9). These findings suggest that upregulation of PD-1 expression may play a central role in tumor mediated immune suppression. Mean expression of PDL-1 was 91% on dendritic cells generated from adherent peripheral blood mononuclear cells obtained from normal volunteers (n=6), and 66% on patient derived myeloma cells (n=3). In addition, PDL-1 expression is found in greater than 90% of DC/tumor fusions (n=2), which potentially provides an inhibitory signal dampening fusion mediated immunologic response. We examined the effect of PD-1 blockade on T cell response to DC/tumor fusions ex vivo with different anti PD-1 antibodies including CT-011. DC/tumor fusions were co-cultured with autologous T cells alone or with antibodies against PD-1 Enhanced fusion mediated stimulation of T cells was noted particularly with CT-011, resulting in a greater than 5 fold increase in T cell proliferation. Interferon gamma secretion by CD4+ T cells in response to stimulation by DC/myeloma fusion cells was increased from 4% to 11% in the presence of CT-011. In addition, IL-10 secretion by CD4+ cells following DC/myeloma fusion stimulation decreased from 6.5% to 3.5% following PD-1 blocakde . In summary, we have demonstrated that PD-1 expression is increased in T cells of patients with hematologic malignancy, and CT-011, a PD-1 blocking antibody, enhances activated T cell responses following stimulation with a DC/tumor fusion vaccine. A clinical trial in which patients with multiple myeloma are treated with DC/myeloma fusions in conjunction with CT-011 following autologous transplantation is planned. Disclosures: Schickler: CureTech, Ltd.: Employment. Rotem-Yehudar:CureTech, Ltd.: Employment.

Immune impact induced by PSA-tricom, a therapeutic vaccine for prostate cancer.

2014 ◽  
Vol 32 (4_suppl) ◽  
pp. 245-245
Author(s):  
Ravi Amrit Madan ◽  
Kwong Yok Tsang ◽  
Caroline Jochems ◽  
Jennifer L. Marte ◽  
Jo A Tucker ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Specific Antigen ◽  
T Cell Responses ◽  
Fold Increase ◽  
Phase Iii ◽  
Cell Responses

245 Background: PSA-TRICOM is a vector-based therapeutic cancer vaccine designed to generate a targeted anti-tumor immune response against prostate-specific antigen (PSA)–expressing tumor cells. Early clinical trials have evaluated the immunologic impact of this vaccine and demonstrated promising clinical activity. PSA-TRICOM is being evaluated in a phase III trial in metastatic castration resistant prostate cancer (mCRPC). Methods: We recently conducted a broad overview of both published and new data which analyzed the immune responses to PSA-TRICOM. Immune responses included ELISPOT for antigen-specific immune response and flow-cytometry analysis of peripheral immune cells. Results: 104 patients (pts) with prostate cancer were tested for T-cell responses and 59 out of 104 (57%) demonstrated a greater than or equal to 2-fold increase in PSA-specific T cells 4 weeks after vaccine. The responders had a median 5-fold increase relative to pre-vaccine levels. For most pts PSA-specific immune responses (likely memory cells) seen 28 days following the most recent vaccine are quantitatively similar to levels of circulating influenza-specific T cells in the same pts. In addition, 19 out of 28 pts (68%) evaluated demonstrated immune responses to tumor-associated antigens not present in the vaccine (antigen spreading). Since PSA-TRICOM is designed to generate a cellular (TH1 immune response), it is not surprising that 2 out of 349 pts (<1.0%) demonstrated evidence of PSA antibody induction following vaccine. This suggests that post-vaccine PSA kinetics were not affected by PSA antibodies. Conclusions: PSA-TRICOM has demonstrated the ability to generate immune responses. Despite these findings, it is important to note that systemic immune response to PSA may underestimate the true therapeutic immune response since it does not measure cells that trafficked to tumor or antigen spreading. Furthermore, while the entire PSA gene is the vaccine, only one epitope of PSA is specifically evaluated in the T-cell responses. Further immune analysis continues in an ongoing phase III of PSA-TRICOM in mCRPC (NCT01322490), accruing worldwide, and two trials combining PSA-TRICOM with enzalutamide (biochemical recurrence/ NCT01875250 and mCRPC/ NCT01867333) currently accruing at NCI. Clinical trial information: multiple trials.

scholarly journals Vaccination regimens incorporating CpG-containing oligodeoxynucleotides and IL-2 generate antigen-specific antitumor immunity from T-cell populations undergoing homeostatic peripheral expansion after BMT

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 450-460 ◽  
Author(s):  
James N. Kochenderfer ◽  
Jessica L. Simpson ◽  
Christopher D. Chien ◽  
Ronald E. Gress
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses ◽  
Peripheral Expansion

Development of CD8+ T-cell responses targeting tumor-associated antigens after autologous stem cell transplantations (ASCTs) might eradicate residual tumor cells and decrease relapse rates. Because thymic function dramatically decreases with aging, T-cell reconstitution in the first year after ASCT in middle-aged patients occurs primarily by homeostatic peripheral expansion (HPE) of mature T cells. To study antigen-specific T-cell responses during HPE, we performed syngeneic bone marrow transplantations (BMTs) on thymectomized mice and then vaccinated the mice with peptides plus CpG-containing oligodeoxynucleotides (CpGs) in incomplete Freund adjuvant and treated the mice with systemic interleukin-2 (IL-2). When CD8+ T-cell responses were measured ex vivo, up to 9.1% of CD8+ T cells were specific for tumor-associated epitopes. These large T-cell responses were generated by synergism between CpG and IL-2. When we injected mice subcutaneously with tumor cells 14 days after BMT and then treated them with peptide + CpG-containing vaccines plus systemic IL-2, survival was increased and tumor growth was inhibited in an epitope-specific manner. Depletion of CD8+ T cells eliminated epitope-specific antitumor immunity. This is the first report to demonstrate that CD8+ T-cell responses capable of executing antitumor immunity can be elicited by CpG-containing vaccines during HPE.

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