Retargeting of anti-viral immune responses to solid tumors using bispecific adapters

2016 ◽  
Vol 61 ◽  
pp. S123
Author(s):  
J. Niemann ◽  
N. Woller ◽  
M.P. Manns ◽  
S. Kubicka ◽  
F. Kühnel
Keyword(s):  
Immune Responses ◽  
Solid Tumors

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

scholarly journals Combining Photodynamic Therapy with Immunostimulatory Nanoparticles Elicits Effective Anti-Tumor Immune Responses in Preclinical Murine Models

Pharmaceutics ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1470
Author(s):  
Ruben Victor Huis in ‘t Veld ◽  
Candido G. Da Silva ◽  
Martine J. Jager ◽  
Luis J. Cruz ◽  
Ferry Ossendorp
Keyword(s):  
T Cells ◽  
Photodynamic Therapy ◽  
Immune Responses ◽  
Solid Tumors ◽  
Cd8 T Cells ◽  
Vaccination Strategy ◽  
Neutrophil Infiltration ◽  
Poly I:C ◽  
Murine Models ◽  
Human Papillomavirus 16

Photodynamic therapy (PDT) has shown encouraging but limited clinical efficacy when used as a standalone treatment against solid tumors. Conversely, a limitation for immunotherapeutic efficacy is related to the immunosuppressive state observed in large, advanced tumors. In the present study, we employ a strategy, in which we use a combination of PDT and immunostimulatory nanoparticles (NPs), consisting of poly(lactic-co-glycolic) acid (PLGA)-polyethylene glycol (PEG) particles, loaded with the Toll-like receptor 3 (TLR3) agonist poly(I:C), the TLR7/8 agonist R848, the lymphocyte-attracting chemokine, and macrophage inflammatory protein 3α (MIP3α). The combination provoked strong anti-tumor responses, including an abscopal effects, in three clinically relevant murine models of cancer: MC38 (colorectal), CT26 (colorectal), and TC-1 (human papillomavirus 16-induced). We show that the local and distal anti-tumor effects depended on the presence of CD8+ T cells. The combination elicited tumor-specific oncoviral- or neoepitope-directed CD8+ T cells immune responses against the respective tumors, providing evidence that PDT can be used as an in situ vaccination strategy against cancer (neo)epitopes. Finally, we show that the treatment alters the tumor microenvironment in tumor-bearing mice, from cold (immunosuppressed) to hot (pro-inflammatory), based on greater neutrophil infiltration and higher levels of inflammatory myeloid and CD8+ T cells, compared to untreated mice. Together, our results provide a rationale for combining PDT with immunostimulatory NPs for the treatment of solid tumors.

Long term results from a phase 1 trial of GEN-009, a personalized neoantigen vaccine, combined with PD-1 inhibition in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2613-2613
Author(s):  
Maura L. Gillison ◽  
Mark M. Awad ◽  
Przemyslaw Twardowski ◽  
Ammar Sukari ◽  
Melissa Lynne Johnson ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Salvage Therapy ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Long Term Results ◽  
Advanced Solid Tumors ◽  
Cell Responses

2613 Background: GEN-009 is an adjuvanted personalized cancer vaccine containing up to 20 neoantigens selected by ATLAS, an ex vivo bioassay screening autologous T cells for immune responses against both neoantigens as well as Inhibigens. Inhibigen-specific T cells suppress immunity and have been shown to accelerate tumor progression in mice and are avoided in GEN-009. In cohort A, all patients immunized in the adjuvant setting with GEN-009 monotherapy developed immune responses. Nearly all (99%) of selected peptides were immunogenic: ex vivo CD4+ and CD8+ fluorospot responses specific for 51% and 41% of immunized peptides, respectively. Seven of 8 patients continue without progression with a median follow up of 18 months. Methods: GEN-009 is being evaluated in patients (pts) with advanced cancer who received standard-of-care (SOC) PD-1 inhibitor as monotherapy or in combination therapy during vaccine manufacturing. Five vaccine doses were administered over 24 weeks in combination with a PD-1 CPI. Patients who progressed prior to vaccination received alternative salvage therapy followed by GEN-009 in combination. Peripheral T cell responses were measured by fluorospot assays in ex vivo and in vitro stimulation. Results: 15 pts received GEN-009 in combination with a PD-1 inhibitor; 1 patient received GEN-009 monotherapy. Median number of neoantigens per vaccine was 14 (5-18). GEN-009-related adverse events were limited to vaccine injection site reactions and mild myalgias or fatigue. Longitudinal evaluation of ex vivo T cell responses revealed that sequential vaccination with GEN-009 had an overall additive effect on the robustness of IFNγ secretion and responses were persistent for at least 6 months in some patients. Epitope spread was detected in CPI sensitive patients, but not in CPI refractory patients receiving salvage therapy. Three patients who responded to PD-1 inhibition followed by disease stabilization then demonstrated further reduction after GEN-009 vaccination that could represent vaccine effect. Eight of 9 CPI responsive patients are progression-free from 3 to 10 months after first vaccine dose. Four of 7 CPI refractory patients have experienced unexpected prolonged stable disease after vaccination of up to 8 months after vaccination. 2 of 2 patients with available samples lost all evidence of circulating tumor DNA including non-targeted neoantigens. Conclusions: Vaccination with GEN-009 in combination with anti-PD-1 CPI in patients with advanced solid tumors shows little additive toxicity. Preliminary data demonstrate induction of broad neoantigen-specific immune responses and epitope spreading in the presence of PD-1 CPI. Broad immunity against tumor specific targets and encouraging patient outcomes support further study. Clinical trial information: NCT03633110.

scholarly journals Analytical Validation of a Next-Generation Sequencing Assay to Monitor Immune Responses in Solid Tumors

2018 ◽  
Vol 20 (1) ◽  
pp. 95-109 ◽  
Author(s):  
Jeffrey M. Conroy ◽  
Sarabjot Pabla ◽  
Sean T. Glenn ◽  
Blake Burgher ◽  
Mary Nesline ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Immune Responses ◽  
Solid Tumors ◽  
Next Generation ◽  
Analytical Validation ◽  
Generation Sequencing

scholarly journals Induction of Micronuclei in Cervical Cancer Treated with Radiotherapy

2020 ◽  
Vol 10 (3) ◽  
pp. 110
Author(s):  
Daijiro Kobayashi ◽  
Takahiro Oike ◽  
Kazutoshi Murata ◽  
Daisuke Irie ◽  
Yuka Hirota ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Immune Responses ◽  
Solid Tumors ◽  
Clinical Evidence ◽  
Median Number ◽  
Peripheral Blood Lymphocytes ◽  
Tumor Biopsy ◽  
Biopsy Specimens ◽  
Pre Treatment ◽  
Sting Pathway

Micronuclei (MN) trigger antitumor immune responses via the cyclic GMP-AMP synthase-signaling effector stimulator of interferon genes (cGAS-STING) pathway. Radiotherapy induces MN in peripheral blood lymphocytes. However, data for solid tumors are lacking. Here, we analyzed MN post-radiotherapy in solid tumor samples. Tumor biopsy specimens were obtained from seven prospectively recruited patients with cervical cancer, before treatment and after receiving radiotherapy at a dose of 10 Gy (in five fractions). The samples were stained with 4′,6-diamidino-2-phenylindole dihydrochloride, and 200 nuclei per sample were randomly identified and assessed for the presence of MN or apoptosis, based on nuclear morphology. The median number of MN-harboring nuclei was significantly greater in samples from patients treated with radiotherapy than in pre-treatment samples (151 (range, 16–327) versus 28 (range, 0–61); p = 0.015). No significant differences in the number of apoptotic nuclei were observed between pre-treatment and 10 Gy samples (5 (range, 0–30) versus 12 (range, 2–30); p = 0.30). This is the first report to demonstrate MN induction by radiotherapy in solid tumors. The results provide clinical evidence of the activation of antitumor immune responses by radiotherapy.

Results of a first-in-human phase I study of INVAC-1, an optimized plasmid DNA encoding an inactive form of human telomerase reverse transcriptase (hTERT), in patients with advanced solid tumors.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3087-3087 ◽  
Author(s):  
Luis Teixeira ◽  
Jacques Medioni ◽  
Ludovic Doucet ◽  
Stephane Culine ◽  
Stephane Oudard ◽  
...  
Keyword(s):  
Immune Responses ◽  
Reverse Transcriptase ◽  
Solid Tumors ◽  
Single Agent ◽  
Human Study ◽  
Telomerase Reverse Transcriptase ◽  
Human Telomerase Reverse Transcriptase ◽  
Inactive Form ◽  
Human Telomerase ◽  
Anti Tumor Activity

3087 Background: INVAC-1 is an optimized plasmid encoding an inactive form of human telomerase reverse transcriptase (hTERT). hTERT is a prototype of shared tumor antigen expressed in more than 85% of human tumors. Telomerase activation is associated with maintenance of telomere length and accounts for the unlimited proliferative capacity of cancer cells. In preclinical models, INVAC-1 triggered Th1-polarized hTERT-specific CD8+ and CD4+T-cell immune responses and anti-tumor effects. Here, we report clinical and pharmacodynamics results of the first clinical study with INVAC-1 as a single agent in solid tumors. Methods: A 3+3 design phase 1 First in Human study evaluating INVAC-1 given monthly for 3 cycles using electroporation-based intra-dermal (ID) injection was conducted. Primary objectives included safety, tolerability and dose limiting toxicities to identify the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Secondary objectives included immune response and anti-tumor activity. Results: 20 patients (pts) with refractory/progressive solid tumors were enrolled in two centers. 3 escalating doses were studied: 100 µg (3 pts), 400 µg (3 pts) and 800 µg (14 pts). At 3-month data cut-off, no dose limiting toxicities or treatment related SAEs have been reported; no MTD was defined. The most common treatment-related adverse events were grade 1 or 2: asthenia and local reaction at injection site. 12 pts experienced stable disease and clinical benefit. For 10 pts, the treatment was extended beyond the per-protocol 3-month duration, up to nine months for 2 pts. IFN-g polarized anti-hTERT immune responses were detected in 55% of pts, in response to INVAC-1 treatment. Conclusions: Results from this study indicate that INVAC-1 ID was safe, well tolerated and strongly immunogenic at the doses and schedule tested. Early anti-tumor activity has been observed. The RP2D of INVAC-1 is therefore a monthly ID injection of 800 µg. These results encourage a future evaluation of INVAC-1 is solid tumors, as well as in hematologic malignancies, either as monotherapy or in combination with various immunotherapeutic drugs. Clinical trial information: NCT02301754.

scholarly journals 521 GEN-009, a personalized neoantigen vaccine candidate, elicits diverse and durable immune responses associated with clinical efficacy outcomes

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A551-A551
Author(s):  
Mara Shainheit ◽  
Ece Bicak ◽  
Masoud Golshadi ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Vaccine Candidate ◽  
Ex Vivo ◽  
T Cell Responses ◽  
T Cell Subsets ◽  
Ki 67 ◽  
Cell Responses

BackgroundGEN-009, a personalized vaccine candidate comprised of ATLAS™-prioritized neoantigens combined with Hiltonol®, is currently being evaluated in a Phase 1/2a clinical trial (NCT03633110). ATLAS™ is a cell-based recall assay that, without predictions, screens each patient‘s mutanome to identify neoantigens for vaccine inclusion and deleterious Inhibigens™ for exclusion. In the Part A monotherapy cohort, vaccine-specific immune responses were generated in all subjects, against 99% of administered peptides.1 Here we characterize immune responses and their association with reduction in tumors in Part B of the study, in which patients were treated with GEN-009 combined with anti-PD-1-based checkpoint inhibitors (CPI).MethodsFourteen adults with solid tumors were enrolled in the study. During the screening and manufacturing period, patients received standard of care anti-PD-1 CPI. Subsequently, patients were immunized with GEN-009 in combination with anti-PD-1. CPI refractory patients received salvage therapy prior to GEN-009. Peripheral blood mononuclear cells were collected at baseline, pre-vaccination (D1), as well as multiple days post first dose. The magnitude and durability of vaccine-induced immune responses were assessed by quantifying neoantigen-specific responses in fluorospot assays. Proliferation of neoantigen-specific T cells and T cell phenotypes were evaluated by flow cytometry. Circulating tumor DNA (ctDNA) levels were monitored pre- and post-GEN-009 dosing to assess its potential as a predictive biomarker.ResultsGEN-009 immunization induced neoantigen-specific T cell responses in all evaluable patients, with ex vivo responses emerging as early as 1 month and persisting up to 366 days in some subjects. Comparing RECIST responders (PR, CR) to non-responders (SD, PD), the median breadth of statistically positive responses to vaccine antigens at day 50 was greater in non-responders ex vivo (29 vs. 75%, respectively), however, by IVS assay the proportions inverted (83% vs. 38%). Longitudinal evaluation of neoantigen-specific responses revealed an association between the magnitude and kinetics of cytokine secretion and increased activated and proliferating Ki-67+ T cells and TEM cells in both T cell subsets. Quantification of ctDNA in a subset of patients supported the RECIST readouts in association with the enhanced neoantigen-specific T cell responses.ConclusionsVaccination with GEN-009 combined with anti-PD-1-based therapy induced early, durable, and neoantigen-specific CD4+ and CD8+ T cell responses with pronounced Ki-67+ and TEM cell populations. Overall, a greater breadth of response to vaccine neoantigens was associated with improved clinical benefit, which was further supported by ctDNA levels. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.ReferencesLam H, et al. An empirical antigen selection method identifies neoantigens that either elicit broad anti-tumor response or drive tumor growth. Cancer Discovery 2021 March; 11(3):696–713.Ethics ApprovalETHICS STATEMENTThis study was approved by Western Institutional Review Board, approval number 1-1078861-1

scholarly journals 476 First-in-human phase 1/2 study of the first-in-class SUMO-activating enzyme inhibitor TAK-981 in patients with advanced or metastatic solid tumors or relapsed/refractory lymphoma: phase 1 results

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A505-A506
Author(s):  
Arkadiusz Dudek ◽  
Dejan Juric ◽  
Afshin Dowlati ◽  
Ulka Vaishampayan ◽  
Hadeel Assad ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Immune Responses ◽  
Solid Tumors ◽  
Cell Activation ◽  
Nk Cell ◽  
Phase 1 ◽  
Phase 2 ◽  
Target Engagement ◽  
Grade 3

BackgroundSUMOylation is a post-translational modification that serves as an important modulator of immune responses via its role in constraining the type I interferon (IFN-1) response. TAK-981 is a small molecule that inhibits SUMOylation and increases IFN-1-dependent innate immune responses with the potential to enhance adaptive immunity. Here, we report dose-escalation data from a TAK-981 Phase 1/2 clinical study (NCT03648372), the first clinical data for a SUMOylation inhibitor.MethodsAdults with advanced/metastatic solid tumors or relapsed/refractory lymphomas received TAK-981 IV twice-weekly (BIW; days 1, 4, 8, 11) or once-weekly (QW; days 1, 8) in 21-day cycles. Dose escalation was guided by a Bayesian Logistic Regression Model (BLRM) with overdose control, plus available pharmacokinetic/pharmacodynamic (PK/PD) data. Phase 1 objectives were to determine TAK-981 safety/tolerability and establish the recommended phase 2 dose (RP2D).ResultsSeventy-six patients received TAK-981 at 10 dose levels (3–40 mg BIW; 60–120 mg QW/BIW). Median age was 61 years (range, 38–79); 42 (55.3%) patients were female. Four dose-limiting toxicities were seen in 62 evaluable patients (transient grade 3 ALT/AST elevation, 60 mg BIW; grade 3 pneumonitis, 90 mg BIW; grade 3 stomatitis and grade 3 cognitive disturbance, 120 mg BIW). Per BLRM, 120 mg BIW was determined to be the maximum tolerated dose. At data cut-off, median treatment duration was 2 cycles (range, 1–12); 13 (17.1%) patients were ongoing. table 1 summarizes TAK-981 safety. The most common (≥20%) treatment-emergent adverse events (TEAEs) were fatigue (42.1%), nausea (39.5%), headache (31.6%), diarrhea (28.9%), pyrexia (27.6%), vomiting (23.7%), decreased appetite (22.4%). Common (≥5%) grade ≥3 TEAEs were hypokalemia (9.2%), anemia (7.9%), lymphocyte count decreased (6.6%), abdominal pain (5.3%). Grade 2 cytokine release syndrome was reported in 4 (5.2%) patients; symptoms resolved within 12–24 hours with supportive oxygen and/or IV fluids. One partial response was observed at 40 mg TAK-981 BIW in a patient with relapsed/refractory HER2-negative, hormone receptor-positive breast cancer. TAK-981 exhibited linear PK, with approximately dose-proportional exposure and a mean terminal half-life of 3.8–10.8 hours at ≥60 mg. Evidence of dose-dependent target engagement (figure 1), and PD (figures 2–4) in blood were observed. The single-agent TAK-981 RP2D was 90 mg BIW.Abstract 476 Table 1Summary of TAK-981 safety profileAbstract 476 Figure 1PD in patients receiving TAK-981 on the BIW schedule: target engagement.Blood samples were collected on Cycle 1 Day 1 pre-dose and at multiple timepoints after TAK-981 administration. Target engagement in T cells was detected by flow cytometry with an antibody recognizing the TAK-981-SUMO adduct formed during the inhibition of the SUMO-activating enzyme by TAK-981; Cycle 1 Day 1 signal increased at 1 hour post-end-of-infusion compared to the background level observed pre-dose.Abstract 476 Figure 2PD in patients receiving TAK-981 on the BIW schedule: SUMOylation.SUMOylation in T cells, detected by flow cytometry with an antibody recognizing SUMO2/3, decreased at 1 hour post-end-of-infusion on Cycle 1 Day 1 compared to pre-dose, indicating that fewer SUMO2/3 chains are formed when the SUMO-activating enzyme is inhibited.Abstract 476 Figure 3PD in patients receiving TAK-981 on the BIW schedule: upregulation of CXCL10 expression.Upregulation of mRNA levels of CXCL10, an IFN-I-regulated gene, in peripheral blood. Gene expression was measured using Nanostring nCounter at Cycle 1 Day 1 pre-dose and at several timepoints post-dose. Data for maximum increase at 8 or 24 hours, relative to pre-dose, is shown.Abstract 476 Figure 4PD in patients receiving TAK-981 on the BIW schedule: NK cell activation.NK cell activation in peripheral blood measured by flow cytometry. Percentage of CD69-positive NK cells at Cycle 1 Day 1 pre-dose and at 24 hours post-end-of-infusion is shown by patient for each dose.ConclusionsThe data generated in this study support continued TAK-981 development for treatment of solid tumors and lymphoma. The Phase 2 study expansion is ongoing in patients with advanced/metastatic non-small-cell lung, cervical, and colorectal cancer, and in relapsed/refractory non-Hodgkin lymphoma.Trial RegistrationClinical Trial identification: ClinicalTrials.gov. Identifier: NCT03648372Ethics ApprovalThe study was approved by the Institutional Review Board or Institutional Ethics Committee of all participating institutions

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