Randomized phase II study of the safety, efficacy, and immune response of GVAX pancreas (with cyclophosphamide) and CRS-207 with or without nivolumab in patients with previously treated metastatic pancreatic adenocarcinoma (STELLAR).

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. TPS486-TPS486 ◽  
Author(s):  
Dung T. Le ◽  
Todd S. Crocenzi ◽  
Jennifer N. Uram ◽  
Eric R. Lutz ◽  
Dan Laheru ◽  
...  
Keyword(s):  
T Cells ◽  
Pancreatic Adenocarcinoma ◽  
Tumor Antigens ◽  
Vaccination Strategy ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Multiple Tumor ◽  
Immunological Responses ◽  
Gm Csf ◽  
Pancreatic Cancer Cells

TPS486 Background: A heterologous prime-boost vaccination strategy using GVAX pancreas and CRS-207 is showing promise in patients with pancreatic adenocarcinoma (PDA) (Le, JCO 2015). Furthermore, blockade of the immune checkpoint programmed death-1 (PD-1) is active in some cancers. Combinatorial strategies aimed at priming tumor antigen-specific T cells while simultaneously blocking negative checkpoints may be necessary to improve outcomes in PDA. GVAX is composed of allogeneic pancreatic cancer cells modified to express GM-CSF and induces a broad response against multiple tumor antigens. GVAX is given with low-dose cyclophosphamide (CY) to inhibit regulatory T cells. CRS-207 is live-attenuated Listeria monocytogenes engineered to express the tumor-associated antigen mesothelin. CRS-207 boosts responses against mesothelin and is unique in its capacity to stimulate both innate and adaptive immunity by activating T cells and NK cells. Nivolumab is an antibody against PD-1. Methods: This is a phase 2 study comparing CY/GVAX and CRS-207 with or without nivolumab in subjects with PDA who failed only one chemotherapy regimen for metastatic disease. Subjects are randomized in a 1:1 ratio to receive either 2 doses of CY/nivolumab/GVAX and 4 doses of nivolumab/CRS-207 (Arm A) or 2 doses of CY/GVAX and 4 doses of CRS-207 (Arm B). The primary objective is to compare OS between Arms A and B. Secondary/exploratory objectives include: assessment of safety and clinical responses (tumor assessments and CA19-9 levels) and correlation of Lm- and mesothelin-specific T cell and other immunological responses with OS, progression-free survival and best overall response. Clinical trial information: NCT02243371.

In Situ Vaccination with TLR9 Agonist Combined with Local Radiation In Mycosis Fungoides: Analysis of Phase I/II Study

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 286-286 ◽  
Author(s):  
Youn H. Kim ◽  
Dita Gratzinger ◽  
Cameron Harrison ◽  
Joshua Brody ◽  
Debra Czerwinski ◽  
...  
Keyword(s):  
T Cells ◽  
Low Dose ◽  
Tumor Antigens ◽  
Vaccination Strategy ◽  
Large Cell ◽  
Low Dose Radiation ◽  
Clinical Responses ◽  
Local Radiation ◽  
Dose Radiation

Abstract Abstract 286 Background: In a murine model, our in situ vaccination therapy combining tumor antigens with TLR9 agonist cured mice of lymphoma. Our phase I/II study in indolent B-cell lymphoma demonstrated that this in situ vaccination maneuver utilizing local radiation to expose tumor antigens combined with CpG ODN was well-tolerated without treatment limiting toxicities. It induced meaningful systemic clinical responses and tumor-reactive memory CD8 T-cells. In parallel, we explored this in situ vaccination strategy in cutaneous T-cell lymphoma (CTCL), specifically mycosis fungoides (MF). Our objectives were to determine the feasibility and safety and to assess the local and systemic antitumor effects in MF. Methods: Patients with MF stages IA-IVA who failed ≥1 standard therapy were eligible. Immunization site was treated with low-dose radiation (2 Gy × 2 d), bracketed by intratumoral injection of CpG followed by weekly intratumoral CpG × 8. Local (immunized site) and systemic antitumor responses were assessed at wk 0, 2, 4, 8, 12, then monthly until PD/off-study. Clinical response was evaluated by assessing skin disease burden at sites not treated with immunization procedure. Results: Study enrollment was completed with total of 15 patients. Median age was 57 yrs (range 18–71 yrs), 12 of 15 were male. Six patients had stage IB and 9 with stage IIB (3 with large-cell transformation). Median number of prior therapies was 5 with range of 2–9. After the initial 6 patients, a second immunization site was added at wk 4 to enhance systemic response. Total of 5 partial responses were observed (30% OR); 2 of 6 treated with single immunization and 3 of 9 with dual immunization. Median time to response was 8 wks (range 4–12 wks), duration of response 7 wks (range 4–44 wks), and time to progression 20+ wks (range 3–44+ wks). Patients with large-cell transformed MF did not respond. Common toxicities were injection site and flu-like symptoms; mostly grade 1–2 and all transient. No clinical or laboratory findings of any autoimmune disorder were observed. Local tissue tumor/immune responses were assessed by immunostaining. CpG + local radiation treated immunization site showed a significant reduction of CD25+, Foxp3+ T-cells (p<0.01) consisting of MF cells and tumor-infiltrating lymphocytes. Similar reduction in S100+, CD1a+ dendritic cells (DCs) was observed post immunization (p < 0.025). A qualitative analysis suggested more remarkable reduction of CD25+ T-cells and skin DCs in clinical responders vs. non-responders (p= 0.058, 0.121). CpG dose-responsive activation of peripheral blood pDCs was observed in vitro. Conclusions: Our novel in situ vaccination strategy using a combination of intratumoral CpG ODN and low-dose radiation is feasible in CTCL/MF with acceptable toxicities. Depletion of tissue T-regs may be observed at immunized sites. Reduction of skin DCs may suggest cross-priming and migration of DCs to regional lymph nodes. Clinical responses in subset of patients and CpG responsiveness of pDCs may warrant further study with modifications to augment therapeutic effects. Disclosures: No relevant conflicts of interest to declare.

Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 345-345 ◽  
Author(s):  
Dung T. Le ◽  
Andrew H. Ko ◽  
Zev A. Wainberg ◽  
Vincent J. Picozzi ◽  
Hedy L. Kindler ◽  
...  
Keyword(s):  
Single Agent ◽  
Dropout Rate ◽  
Primary Objective ◽  
Gm Csf ◽  
Pancreatic Cancer Cells ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Phase 2 Study ◽  
High Dropout Rate ◽  
Previously Treated ◽  
To Receive

345 Background: GVAX is composed of irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and induce broad tumor antigen responses. Low-dose cyclophosphamide (CY) is administered with GVAX to inhibit regulatory T cells. CRS-207 is live, attenuated, double-deleted Listeria monocytogenes(LADD) engineered to express mesothelin. CRS-207 boosts T cell responses against mesothelin and stimulates innate and adaptive immunity. In an earlier Phase 2 study in patients with mPDA, CY/GVAX + CRS-207 resulted in a significant improvement in overall survival (OS) compared to CY/GVAX alone. Methods: Patients with previously-treated mPDA were randomized 1:1:1 to receive 2 doses of CY/GVAX + 4 doses of CRS-207 (Arm A), 6 doses of CRS-207 alone (Arm B), or physician’s choice of single-agent chemotherapy (Arm C). Two cohorts were included based on number of prior lines of therapy; the primary cohort (PC) represented those with ≥ 2 prior lines. The primary objective was to compare OS between Arms A and C in the PC. Additional objectives include OS analyses between all treatment arms, safety, tumor responses and immune analyses. Results: 303 patients were enrolled: 213 in the PC and 90 in an exploratory 2nd-line cohort (SC). Common AEs associated with CRS-207 treatment included transient fevers, chills, and nausea. High dropout rates were observed in Arm C prior to treatment (40% in PC, 63% in SC). Clinical trial information: NCT02004262 . Subset and immune analyses, as well as OS data from SC, will be presented at the meeting. Conclusions: The combination of CY/GVAX + CRS-207 did not show a survival benefit over chemotherapy in patients with previously-treated mPDA, although survival of patients receiving CRS-207 alone appeared similar to chemotherapy. The regimens were well tolerated with no new significant safety findings. The high dropout rate in the chemotherapy arm demonstrates a potential challenge for conventional controls in immunotherapy trials. [Table: see text]

A phase IIb, randomized, controlled, multicenter, open-label study of the efficacy and immune response of GVAX pancreas vaccine and CRS-207 compared to chemotherapy or to CRS-207 alone in adults with previously treated metastatic pancreatic adenocarcinoma (ECLIPSE Study).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS489-TPS489 ◽  
Author(s):  
Dung T. Le ◽  
Andrea Wang-Gillam ◽  
Vincent J. Picozzi ◽  
Todd S. Crocenzi ◽  
Michael Morse ◽  
...  
Keyword(s):  
T Cells ◽  
Pancreatic Adenocarcinoma ◽  
Metastatic Disease ◽  
Single Agent ◽  
P Value ◽  
Prior Chemotherapy ◽  
Pancreatic Cancer Cells ◽  
Metastatic Pancreatic Adenocarcinoma ◽  
Clinical Responses ◽  
Previously Treated

TPS489 Background: A prime-boost vaccination strategy using GVAX pancreas vaccine and CRS-207 is showing activity in patients with metastatic pancreatic adenocarcinoma (PDA). GVAX is composed of lethally-irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF. GVAX induces a response against multiple tumor antigens and is given after low-dose cyclophosphamide (CY) to inhibit regulatory T cells. CRS-207 is live-attenuated Listeria monocytogenes engineered to express the tumor-associated antigen mesothelin. CRS-207 boosts responses against mesothelin and stimulates both innate and adaptive immunity by activating T cells and NK cells. Results from a phase 2 study demonstrated CY/GVAX plus CRS-207 improved overall survival (OS) compared to CY/GVAX alone (p-value<0.05; Le, GI ASCO 2014). Methods: This is a phase 2b study comparing CY/GVAX and CRS-207 to chemotherapy or to CRS-207 alone in patients with previously-treated metastatic PDA. Patients will be enrolled in two cohorts: 150 patients into a primary cohort of patients with at least two prior chemotherapy regimens for metastatic disease (third + line) and 90 patients into an exploratory cohort of patients with only one prior chemotherapy regimen for metastatic disease (second line). Patients will be randomized in a 1:1:1 ratio to receive 2 doses of CY/GVAX and 4 doses of CRS-207 (Arm A), six doses of CRS-207 (Arm B) or physician’s choice of single-agent chemotherapy (Arm C). The primary objective is to compare OS between Arms A and C in the primary cohort. Secondary/exploratory objectives include: comparison of OS in both primary and exploratory cohorts between all treatment arms, assessment of safety and clinical responses (tumor assessments and CA19-9 levels) and correlation of Lm- and mesothelin-specific T cell and other immunological responses with clinical responses. Updated enrollment will be reported. (Sponsor: Aduro BioTech, Inc.; NCT02004262). Clinical trial information: NCT02004262.

A Dendritic Cell Based Vaccination Strategy Geared towards Eradication of Leukemic Stem Cells.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2046-2046
Author(s):  
Hetty J Bontkes ◽  
Jurjen Ruben ◽  
Willemijn van den Ancker ◽  
Theresia M Westers ◽  
G. Ossenkoppele ◽  
...  
Keyword(s):  
Stem Cells ◽  
T Cells ◽  
Tumor Antigens ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Vaccination Strategy ◽  
Leukemic Stem Cells ◽  
Cell Immunity

Abstract Abstract 2046 Poster Board II-23 Introduction: In the majority of cases, initial remission of acute myeloid leukemia (AML) is reached but unfortunately relapse rates remain high and therefore novel treatments are needed. It is thought that recurrent AML originates from chemotherapy resistant quiescent leukemic stem cells (LSC). The application of immunotherapeutic approaches to eradicate LSC remaining after first line chemotherapy may contribute to improved disease outcome. Vaccination strategies have often used dendritic cells (DC) ex vivo pulsed with tumor-derived whole lysates or peptides as modalities to present a broad range of tumor antigens to T cells to stimulate effective anti-tumor T-cell immunity in vivo. It is likely that certain proteins expressed by LSC have a distinct antigenicity as compared to more mature AML blasts and thus provide targets for specific T-cells. Even without identification of specific antigens, LSC can be a useful source of tumor antigens in DC vaccination-based immunotherapy. CD34+CD38- LSC can be identified using malignant stem cell associated cell surface markers including CLL-1 and lineage markers such as CD7, CD19 and CD56. However, the low frequency of these cells precludes the use of LSC derived apoptotic cells or lysates for DC loading. Alternatively, mRNA isolated from LSC can be amplified and subsequently transfected into DC. Materials and Methods: We have made use of the CD38- AML derived cell line MUTZ-3 which contains a subpopulation of CD34+CLL1+ cells which resembles the phenotype of a putative LSC. CLL1+CD34+ and CLL1-CD34- cells were isolated by FACS sorting and total RNA was isolated. mRNA was converted to cDNA and amplified by PCR using the SMART system. Subsequently, mRNA was in vitro transcribed from the amplified cDNA. Mature monocyte derived DC (MoDC) were generated from healthy donor blood and transfected with amplified CLL1+CD34+ derived mRNA and used to stimulate autologous CD8β+ T-cells. After three weekly re-stimulations with CLL1+CD34+ mRNA transfected DC, specificity of the T-cells was analyzed by intracellular IFNγ staining upon 5 hour stimulation with autologous immature MoDC transfected with GFP mRNA, mRNA amplified from unsorted, CLL1+CD34+ or CLL1-CD34- MUTZ-3 subpopulations. Results: Amplification of CLL1 and survivin (also expressed by MUTZ-3) transcripts was confirmed by RT-PCR. After 3 weekly re-stimulations with CLL1+CD34+ amplified RNA transfected DC, 0.04% (range 0.01-0.12%) of the T-cells were positive for IFNγ upon a 5 hr re-stimulation with GFP transfected DC. 0.44% (range 0.04-0.69%) of the T-cells responded to DC transfected with unsorted MUTZ-3 amplified mRNA (p<0.00005 versus GFP control, 2-sided student's T-test), 0.51% (range 0.24-1.35%) responded to DC transfected with CLL1+CD34+ amplified mRNA (p<0.005 versus GFP control) and 0.46% (range 0.24-0.94%) responded to DC transfected with CLL1-CD34- amplified mRNA (p<0.0001 versus GFP control). Conclusion: We show that MoDC transfected with RNA amplified from one MUTZ-3 sub-population resembling the phenotype of LCS cells are capable of inducing T-cells which recognize both cells transfected with mRNA from the LSC resembling MUTZ-3 subset as well as the CLL1-CD34- subset. We are currently testing the efficacy and feasibility of this approach in an autologous setting in vitro. CD8β+ T-cells are stimulated with autologous MoDC from AML patients transfected with amplified mRNA isolated from their own LSC enriched populations. The capacity of these T-cells to kill autologous AML blasts and LSC is subsequently analysed in a 6-colour FACS based cytotoxicity assay. Disclosures: No relevant conflicts of interest to declare.

Actr Platform As an Adaptable, Universal T Cell Therapy That Can Target Multiple Tumor Antigens to Overcome Antigen Escape

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3362-3362
Author(s):  
Greg Motz ◽  
Eugene Choi ◽  
Tooba Cheema ◽  
Taylor Friedman ◽  
Taylor Hickman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Tumor Targeting ◽  
Tumor Antigens ◽  
T Cell Therapy ◽  
Multiple Tumor ◽  
Car T ◽  
Antigen Loss

Abstract Adoptive T-cell therapy with single-chain variable fragment (scFv)-derived chimeric antigen receptors (CARs) has transformed cancer therapy. Nevertheless, treatment failure can occur and is often associated with loss of the targeted antigen-an outcome affecting nearly 65% of patients that have failed CD19-targeted CAR T cell therapy (1). Targeting more than one tumor antigen expressed on the surface of tumor cells to mitigate antigen loss is a strategy that has been tested preclinically with CAR-T therapy. This approach is challenging due to the complexities of validating numerous CAR constructs or generating functional CARs which contain several tandem scFvs. The Antibody-Coupled T-cell Receptor (ACTR) platform is a universal, engineered T-cell therapy technology developed to mediate anti-tumor activity in combination with tumor-targeting antibodies. The ACTR construct, derived from human CD16 and coupled to T-cell signaling domains, is designed to engage the Fc domain of therapeutic antibodies, resulting in a novel platform for T-cell targeted cancer therapy. In contrast to CAR T-cell constructs that are restricted to a single antigen, the ACTR platform is highly adaptable, which can be targeted against a diverse set of tumor antigens-thus circumventing the need to generate and characterize multiple CAR-T therapeutics. We first determined whether ACTR expressing T cells could be combined with a diverse array of tumor-targeting antibodies directed against B cell malignancies. Using cell lines derived from B cell lymphomas or multiple myeloma, we found that ACTR-expressing T cells could be activated with antibodies against multiple B-cell targets including CD19, CD20, CD22, CD38, and CS1. One approach to address CD19 antigen loss in patients relapsing following CD19 CAR-T therapy is to treat with a CD22 CAR-T therapy (2). Given that ACTR can be paired with single antibodies as described above, a flexible sequential administration of targeted antibodies could be utilized. However, we also sought to determine whether combinations of antibodies against CD19 and CD22, when used concurrently, could improve ACTR-activity. We found that dual antigen targeting with anti-CD19 and anti-CD22 antibodies could enhance both ACTR-mediated cytotoxicity and cytokine production in an antibody dose-dependent manner. Taken together, our results provide preclinical evidence for ACTR as a universal, chimeric receptor that could engage multiple tumor antigens with potential to improve patient outcomes by eliminating antigen negative relapse. References 1. Grupp SA, et al. 681 Durable Remissions in Children with Relapsed/Refractory ALL Treated with T Cells Engineered with a CD19-Targeted Chimeric Antigen Receptor (CTL019). ASH. Dec 2015 2. Xinqiao Hospital of Chongqin. Anti-CD22 CAR-T Therapy for CD19-refractory or Resistant Lymphoma Patients.https://www.clinicaltrials.gov/ct2/show/NCT02721407 Disclosures Motz: Unum Therapeutics: Employment. Choi:Unum Therapeutics: Employment. Cheema:Unum Therapeutics: Employment. Friedman:Unum Therapeutics: Employment. Hickman:Unum Therapeutics: Employment. Nelson:Unum Therapeutics: Employment. Shin:Unum Therapeutics: Employment. Boomer:Unum Therapeutics: Employment. Hemphill:Unum Therapeutics: Employment. McGinness:Unum Therapeutics: Employment. Huet:Unum Therapeutics: Employment. Ettenberg:Unum Therapeutics: Employment.

A phase II randomized, double-blinded, placebo-controlled study to evaluate the efficacy and safety of simtuzumab (GS-6624) combined with gemcitabine as first-line treatment for metastatic pancreatic adenocarcinoma.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS4149-TPS4149
Author(s):  
Al Bowen Benson ◽  
Zung Thai ◽  
Michael J. Hawkins ◽  
Douglas Werner ◽  
Hua Dong ◽  
...  
Keyword(s):  
Pancreatic Adenocarcinoma ◽  
Lysyl Oxidase ◽  
Objective Response ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Response To Treatment ◽  
Controlled Study ◽  
Double Blind ◽  
Phase 2 Trial ◽  
Metastatic Pancreatic Adenocarcinoma

TPS4149 Background: Lysyl oxidase-like molecule 2 (LOXL2) is an extracellular matrix enzyme that catalyzes the covalent cross-linking of collagen and is widely expressed across desmoplastic tumors. Simtuzumab (GS-6624) is a humanized antibody that specifically inhibits LOXL2 enzymatic activity. Inhibiting LOXL2 is expected to block formation of desmoplasia, which is thought to play an important role in tumor progression and metastasis. Methods: The primary objective and of the study is to compare the additive efficacy of simtuzumab vs. placebo in combination with gemcitabine as measured by improvement in progression free survival (PFS). The secondary objective is to compare the additive efficacy of simtuzumab vs. placebo as measured by overall survival (OS) and objective response rate. Study Design: The study is a randomized, double-blind, placebo controlled Phase 2 trial in subjects with metastatic pancreatic adenocarcinoma. A total of 234 subjects will be randomized to 200 mg simtuzumab, 700 mg simtuzumab, or placebo at a 1:1:1 ratio (78 subjects per treatment group) in combination with gemcitabine in cycles of 28 days. In each cycle, subjects will receive IV GS-6624 or placebo infused on Days 1 and 15, and IV gemcitabine (1000 mg/m2) on Days 1, 8, and 15. CT or MRI scans will be performed every 8 weeks to evaluate response to treatment. Subjects will continue courses of treatment every 28 days in the absence of disease progression or unacceptable toxicity. As of January 30, 2013, 162 subjects have been randomized. Clinical trial information: NCT01472198.

A randomized pilot study of concurrent docetaxel plus vaccine versus vaccine alone in metastatic androgen independent prostate cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2531-2531
Author(s):  
P. M. Arlen ◽  
J. L. Gulley ◽  
C. Parker ◽  
L. Skarupa ◽  
M. Pazdur ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
T Cell ◽  
Immune Responses ◽  
Tumor Antigens ◽  
Specific Antigen ◽  
Recombinant Vaccinia Virus ◽  
Primary Objective ◽  
Historical Control ◽  
Gm Csf ◽  
To Receive

2531 Background: Docetaxel has activity against androgen insensitive prostate cancer (AIPC) and preclinical studies have demonstrated that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine: if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to a prostate cancer vaccine in patients with metastatic AIPC; secondary endpoints werewhether vaccine could be given safely with docetaxel, and the clinical outcome of the treatment regimen. Methods: The vaccination regimen was composed of (1) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (2) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (3) sequential booster vaccinations with recombinant fowlpox virus containing the PSA gene (rF-PSA). Patients received GM-CSF with each vaccination. Twenty-eight patients with metastatic AIPC were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. An ELISPOT assay for IFN-gamma production was used to monitor immune responses for PSA-specific T cells. Results: The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer associated tumor antigens were also detected post-vaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median PFS on docetaxel was 6.1 months after receiving vaccine compared to 3.7 months with the same regimen in a historical control. Conclusions: This is the first clinical trial to demonstrate that docetaxel can be administered safely with immunotherapy, and without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings. No significant financial relationships to disclose.

scholarly journals Viral Molecular Mimicry Influences the Antitumor Immune Response in Murine and Human Melanoma

2020 ◽  
Author(s):  
Jacopo Chiaro ◽  
Henna Kasanen ◽  
Thomas Whalley ◽  
Cristian Capasso ◽  
Mikaela Gronholm ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cancer Vaccine ◽  
Tumor Antigens ◽  
Vaccine Development ◽  
Molecular Mimicry ◽  
Progression Free Survival ◽  
Cell Clones ◽  
High Level

Molecular mimicry is known to be one of the leading mechanisms by which infectious agents may induce autoimmunity. However, whether a similar mechanism triggers anti-tumor immune response is unexplored, and the role of anti-viral T-cells infiltrating the tumor has remained anecdotal. To address this question, we first developed a bioinformatic tool to identify tumor peptides with high similarity to viral epitopes. Using peptides identified by this tool, we showed that, in mice, viral pre-existing immunity enhanced the efficacy of cancer immunotherapy via molecular mimicry. Specifically, when treated with a cancer vaccine consisting of peptides with a high degree of homology with specific viral peptides, the mice with induced pre-existing immunity to these viral peptides showed significantly better anti-tumor response. To understand whether this mechanism could partly explain immunotherapy-response in humans, we analyzed a cohort of melanoma patients undergoing PD1 treatment with high IgG titer for Cytomegalovirus (CMV). In this cohort of patients, we showed that high level of CMV-antibodies was associated with a prolonged progression free survival, and found that in some cases PBMCs could cross-react with both melanoma and CMV homologous peptides. Finally, T cell TCR sequencing revealed expansion of the same CD8+ T-cell clones, when PBMCs were pulsed with tumor- or homologous viral peptides. In conclusion, we have demonstrated that pre-existing immunity and molecular mimicry could explain part of the response observed in immunotherapy. Most importantly, we have developed a tool able to identify tumor antigens and neoantigens based on their similarity to pathogen antigens, in order to exploit molecular mimicry and cross-reactive T-cells in cancer vaccine development.

scholarly journals Cross-Priming of Naive Cd8 T Cells against Melanoma Antigens Using Dendritic Cells Loaded with Killed Allogeneic Melanoma Cells

2000 ◽  
Vol 192 (11) ◽  
pp. 1535-1544 ◽  
Author(s):  
Frederic Berard ◽  
Patrick Blanco ◽  
Jean Davoust ◽  
Eve-Marie Neidhart-Berard ◽  
Mahyar Nouri-Shirazi ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Tumor Antigens ◽  
Cytotoxic T Lymphocyte ◽  
Melanoma Cells ◽  
Autologous Tumor ◽  
Multiple Tumor ◽  
Melanoma Antigens

The goal of tumor immunotherapy is to elicit immune responses against autologous tumors. It would be highly desirable that such responses include multiple T cell clones against multiple tumor antigens. This could be obtained using the antigen presenting capacity of dendritic cells (DCs) and cross-priming. That is, one could load the DC with tumor lines of any human histocompatibility leukocyte antigen (HLA) type to elicit T cell responses against the autologous tumor. In this study, we show that human DCs derived from monocytes and loaded with killed melanoma cells prime naive CD45RA+CD27+CD8+ T cells against the four shared melanoma antigens: MAGE-3, gp100, tyrosinase, and MART-1. HLA-A201+ naive T cells primed by DCs loaded with HLA-A201− melanoma cells are able to kill several HLA-A201+ melanoma targets. Cytotoxic T lymphocyte priming towards melanoma antigens is also obtained with cells from metastatic melanoma patients. This demonstration of cross-priming against shared tumor antigens builds the basis for using allogeneic tumor cell lines to deliver tumor antigens to DCs for vaccination protocols.

scholarly journals CTIM-26. PATIENT-SPECIFIC DENDRITIC CELL VACCINE (DC-ATA) PULSED WITH ANTIGENS FROM SELF-RENEWING AUTOLOGOUS TUMOR CELLS IN THE TREATMENT OF NEWLY-DIAGNOSED GLIOBLASTOMA: A PHASE II TRIAL

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii39
Author(s):  
Daniela Bota ◽  
David Piccioni ◽  
R LaRocca ◽  
Christopher Duma ◽  
Santosh Kesari ◽  
...  
Keyword(s):  
Phase Ii ◽  
Tumor Antigens ◽  
Dendritic Cell Vaccine ◽  
Primary Objective ◽  
Patient Specific ◽  
Cell Vaccine ◽  
Autologous Tumor ◽  
Gm Csf ◽  
Newly Diagnosed Glioblastoma ◽  
Intent To Treat

Abstract GBM standard treatment is associated with poor survival. Adjunctive therapy with patient-specific vaccines may improve outcomes by enhancing anti-GBM immune responses. A multi-institutional phase II clinical trial was designed with a primary objective of 75% survival 15 months after intent-to-treat enrollment. IL-4 and GM-CSF were used to generate dendritic cells (DC) from monocytes. DC were incubated with autologous tumor antigens (ATA) from the lysate of cultured GBM cells to produce each patient-specific DC-ATA vaccine. Each dose was admixed with 500 mcg GM-CSF at the time of subcutaneous injections at weeks 1, 2, 3, 8, 12, 16, 20 and 24. Enrollment has been completed in April 2020 (n=60). Three patients withdrew from the study prior to starting treatment leaving 57 patients for whom data is available. So far 57 patients have received 344 doses; 27 have completed all 8 doses, 11 received fewer than 8 doses at the time they discontinued treatment, 19 are currently in treatment. No patient has discontinued treatment because of toxicity. 9 pt had died and the preliminary 12 months overall survival is 74%. In a preliminary serologic analysis 12 of 16 patients (75%) had an increase in markers associated with Th1/NK, Th2/immunoglobulins, and Th2 hypersensitivity (eotaxins, IgE and IL17F) by week-3; 9 of 15 (60%) had a decrease in angiogenesis factors, growth factors, and tumor markers by week-8. Immunologic data for all 55 patients who received at least two injections will be available November 2020. This patient-specific DC-ATA immunotherapy approach is feasible, is associated with changes in serologic markers, and may be increasing intratumor inflammation that may be associated with on-target toxicity and efficacy. A interim survival analysis will be conducted in mid-October 2020, 15 months after the 28th patient was enrolled; results will be available November 2020 [Clinicaltrials.gov NCT03400917].

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