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Journal For Immunotherapy of Cancer Jun 2019Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8 T cell responses, whereas addition of an incomplete Freund's adjuvant (IFA) would reduce magnitude and persistence of immune responses.
PATIENTS AND METHODS
Participants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).
RESULTS
Fifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.
CONCLUSIONS
LPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.
TRIAL REGISTRATION
The clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.
Topics: Adjuvants, Immunologic; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Female; Freund's Adjuvant; Humans; Lipids; Lipopolysaccharides; Male; Melanoma; Poly I-C; Polylysine; Toll-Like Receptors; Vaccines, Subunit
PubMed: 31248461
DOI: 10.1186/s40425-019-0625-x -
Frontiers in Immunology 2019Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies....
The Reversal of Immune Exclusion Mediated by Tadalafil and an Anti-tumor Vaccine Also Induces PDL1 Upregulation in Recurrent Head and Neck Squamous Cell Carcinoma: Interim Analysis of a Phase I Clinical Trial.
Myeloid Derived suppressor cells (MDSCs) play a key role in the progression and recurrence of human malignancies and in restraining the efficacy of adjuvant therapies. We have previously shown that Tadalafil lowers MDSCs and regulatory T cells (Treg) in the blood and in the tumor, primes a tumor specific immune response, and increases the number of activated intratumoral CD8T cells in patients with primary Head and Neck Squamous Cell Carcinoma (HNSCC). However, despite these important immune modulatory actions, to date no clinically significant effects have been reported following PDE5 inhibition. Here we report for the first time interim results of our ongoing phase I clinical trial (NCT02544880) in patients with recurrent HNSCC to evaluate the safety of and immunological effects of combining Tadalafil with the antitumor vaccine composed of Mucin1 (MUC1) and polyICLC. The combined treatment of Tadalafil and MUC1/polyICLC vaccine was well-tolerated with no serious adverse events or treatment limiting toxicities. Immunologically, this trial also confirms the positive immunomodulation of Tadalafil in patients with recurrent HNSCC and suggests an adjuvant effect of the anti-tumor vaccine MUC1/polyICLC. Additionally, image cytometry analysis of scanned tumors indicates that the PDE5 inhibitor Tadalafil in conjunction with the MUC1/polyICLC vaccine effectively reduces the number of PDL1macrophages present at the tumor edge, and increases the number of activated tumor infiltrating T cells, suggesting reversion of immune exclusion. However, this analysis shows also that CD163 negative cells within the tumor upregulate PDL1 after treatment, suggesting the instauration of additional mechanisms of immune evasion. In summary, our data confirm the safety and immunologic potential of PDE5 inhibition in HNSCC but also point to PDL1 as additional mechanism of tumor evasion. This supports the rationale for combining checkpoint and PDE5 inhibitors for the treatment of human malignancies.
Topics: B7-H1 Antigen; Biomarkers; Cancer Vaccines; Combined Modality Therapy; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Immunomodulation; Kaplan-Meier Estimate; Myeloid-Derived Suppressor Cells; Neoplasm Staging; Squamous Cell Carcinoma of Head and Neck; Tadalafil; Treatment Outcome
PubMed: 31214178
DOI: 10.3389/fimmu.2019.01206 -
Journal of Vascular and Interventional... Jul 2019To evaluate the therapeutic efficacy of irreversible electroporation (IRE) combined with the intratumoral injection of the immunogenic adjuvant poly-ICLC...
PURPOSE
To evaluate the therapeutic efficacy of irreversible electroporation (IRE) combined with the intratumoral injection of the immunogenic adjuvant poly-ICLC (polyinosinic-polycytidylic acid and poly-L-lysine, a dsRNA analog mimicking viral RNA) inmediately before IRE.
MATERIALS AND METHODS
Mice and rabbits bearing hepatocellular carcinoma tumors (Hepa.129 and VX2 tumor models, respectively) were treated with IRE (2 pulses of 2500V), with poly-ICLC, or with IRE + poly-ICLC combination therapy. Tumor growth in mice was monitored using a digital caliper and by computed tomography in rabbits.
RESULTS
Intratumoral administration of poly-ICLC immediately before IRE elicited shrinkage of Hepa.129 cell-derived tumors in 70% of mice, compared to 30% and 26% by poly-ICLC or IRE alone, respectively (P = .0004). This combined therapy induced the shrinkage of VX-2-based hepatocellular carcinoma tumors in 40% of rabbits, whereas no response was achieved by either individual treatment (P = .045). The combined therapy activated a systemic antitumor response able to inhibit the growth of other untreated tumors.
CONCLUSIONS
IRE treatment, immediately preceded by the intratumoral administration of an immunogenic adjuvant such as poly-ICLC, might enhance the antitumor effect of the IRE procedure. This combination might facilitate the induction of a long-term systemic response to prevent tumor relapses and the appearance of metastases.
Topics: Adjuvants, Immunologic; Animals; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Cell Line, Tumor; Electroporation; Injections, Intralesional; Liver Neoplasms, Experimental; Mice, Inbred C3H; Poly I-C; Polylysine; Rabbits; Tumor Burden
PubMed: 31101416
DOI: 10.1016/j.jvir.2019.02.023 -
Frontiers in Immunology 2019Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if... (Randomized Controlled Trial)
Randomized Controlled Trial
Toll-like receptor-3 agonist Poly-ICLC has been known to activate immune cells and induce HIV replication in pre-clinical experiments. In this study we investigated if Poly-ICLC could be used for disrupting HIV latency while simultaneously enhancing innate immune responses. This was a randomized, placebo-controlled, double-blinded trial in aviremic, cART-treated HIV-infected subjects. Participants ( = 15) were randomized 3:1 to receive two consecutive daily doses of Poly-ICLC (1.4 mg subcutaneously) vs. placebo. Subjects were observed for adverse events, immune activation, and viral replication. Besides primary outcomes of safety and tolerability, several longitudinal immune parameters were evaluated including immune cell phenotype and function via flowcytometry, ELISA, and transcriptional profiling. PCR assays for plasma HIV-1 RNA, CD4 T cell-associated HIV-1 RNA, and proviral DNA were performed to measure HIV reservoirs and latency. Poly-ICLC was overall safe and well-tolerated. Poly-ICLC-related adverse events were Grade 1/2, with the exception of one Grade 3 neutropenia which was short-lived. Mild Injection site reactions were observed in nearly all participants in the Poly-ICLC arm. Transcriptional analyses revealed upregulation of innate immune pathways in PBMCs following Poly-ICLC treatment, including strong interferon signaling accompanied by transient increases in circulating IP-10 (CXCL10) levels. These responses generally peaked by 24-48 h after the first injection and returned to baseline by day 8. CD4 T cell number and phenotype were unchanged, plasma viral control was maintained and no significant effect on HIV reservoirs was observed. These finding suggest that Poly-ICLC could be safely used for inducing transient innate immune responses in treated HIV subjects indicating promise as an adjuvant for HIV therapeutic vaccines. www.ClinicalTrials.gov, identifier: NCT02071095.
Topics: Adult; CD4-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Double-Blind Method; Female; HIV; HIV Infections; Humans; Immunity, Innate; Male; Middle Aged; Poly I-C; Polylysine; Toll-Like Receptor 3
PubMed: 31024557
DOI: 10.3389/fimmu.2019.00725 -
Cancers Apr 2019Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with...
Immunotherapy, including therapeutic vaccines, is increasingly being developed for patients with high-grade glioma, and combinations of immunotherapies and synergy with standard of care are being investigated. In this regard, bevacizumab (BEV) has been shown to synergize with immunotherapy in preclinical studies of glioma and in other tumour entities. Here, we conducted a post-hoc exploratory study to evaluate the effect of the IMA950/poly-ICLC peptide vaccine on subsequent BEV administration in high-grade glioma patients. 16 IMA950-vaccinated and 40 non-vaccinated patients were included. At initial diagnosis, patients benefited from surgery and chemoradiation. At first or subsequent recurrence, patients received 10mg/kg of BEV every 2-3 weeks. Primary endpoints were overall survival (OS) and progression-free survival (PFS) from BEV initiation. IMA950-vaccinated patients did not show improved response to BEV as compared to non-vaccinated patients: there was no difference in median PFS (2.6 vs. 4.2 months for vaccinated and control patients, respectively, = 0.50) nor in median OS (7.8 vs. 10.0 months for vaccinated and control patients, respectively, = 0.69). In conclusion, potential synergy of BEV and therapeutic vaccines, when administered sequentially, has yet to be established in the clinical setting of GBM recurrence. Potential synergy of concomitant administration should be tested in future trials.
PubMed: 30986995
DOI: 10.3390/cancers11040464 -
Nature Medicine May 2019Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently...
Indolent non-Hodgkin's lymphomas (iNHLs) are incurable with standard therapy and are poorly responsive to checkpoint blockade. Although lymphoma cells are efficiently killed by primed T cells, in vivo priming of anti-lymphoma T cells has been elusive. Here, we demonstrate that lymphoma cells can directly prime T cells, but in vivo immunity still requires cross-presentation. To address this, we developed an in situ vaccine (ISV), combining Flt3L, radiotherapy, and a TLR3 agonist, which recruited, antigen-loaded and activated intratumoral, cross-presenting dendritic cells (DCs). ISV induced anti-tumor CD8 T cell responses and systemic (abscopal) cancer remission in patients with advanced stage iNHL in an ongoing trial ( NCT01976585 ). Non-responding patients developed a population of PD1CD8 T cells after ISV, and murine tumors became newly responsive to PD1 blockade, prompting a follow-up trial of the combined therapy. Our data substantiate that recruiting and activating intratumoral, cross-priming DCs is achievable and critical to anti-tumor T cell responses and PD1-blockade efficacy.
Topics: Adult; Aged; Animals; Antigen Presentation; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Cell Line, Tumor; Combined Modality Therapy; Dendritic Cells; Female; Humans; Immunotherapy, Adoptive; Lymphoma, B-Cell; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Poly I-C; Polylysine; Programmed Cell Death 1 Receptor; Toll-Like Receptor 3; Vaccination
PubMed: 30962585
DOI: 10.1038/s41591-019-0410-x -
Neuro-oncology Jul 2019Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we...
BACKGROUND
Peptide vaccines offer the opportunity to elicit glioma-specific T cells with tumor killing ability. Using antigens eluted from the surface of glioblastoma samples, we designed a phase I/II study to test safety and immunogenicity of the IMA950 multipeptide vaccine adjuvanted with poly-ICLC (polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose) in human leukocyte antigen A2+ glioma patients.
METHODS
Adult patients with newly diagnosed glioblastoma (n = 16) and grade III astrocytoma (n = 3) were treated with radiochemotherapy followed by IMA950/poly-ICLC vaccination. The first 6 patients received IMA950 (9 major histocompatibility complex [MHC] class I and 2 MHC class II peptides) intradermally and poly-ICLC intramuscularly (i.m.). After protocol amendment, IMA950 and poly-ICLC were mixed and injected subcutaneously (n = 7) or i.m. (n = 6). Primary endpoints were safety and immunogenicity. Secondary endpoints were overall survival, progression-free survival at 6 and 9 months, and vaccine-specific peripheral cluster of differentiation (CD)4 and CD8 T-cell responses.
RESULTS
The IMA950/poly-ICLC vaccine was safe and well tolerated. Four patients presented cerebral edema with rapid recovery. For the first 6 patients, vaccine-induced CD8 T-cell responses were restricted to a single peptide and CD4 responses were absent. After optimization of vaccine formulation, we observed multipeptide CD8 and sustained T helper 1 CD4 T-cell responses. For the entire cohort, CD8 T-cell responses to a single or multiple peptides were observed in 63.2% and 36.8% of patients, respectively. Median overall survival was 19 months for glioblastoma patients.
CONCLUSION
We provide, in a clinical trial, using cell surface-presented antigens, insights into optimization of vaccines generating effector T cells for glioma patients.
TRIAL REGISTRATION
Clinicaltrials.gov NCT01920191.
Topics: Adult; Aged; Astrocytoma; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Chemoradiotherapy; Combined Modality Therapy; Female; Follow-Up Studies; Glioblastoma; Humans; Male; Middle Aged; Peptides; Poly I-C; Polylysine; Prognosis; Survival Rate; Vaccines, Subunit; Young Adult
PubMed: 30753611
DOI: 10.1093/neuonc/noz040 -
The efficacy of poly-ICLC against Ebola-Zaire virus (EBOV) infection in mice and cynomolgus monkeys.Antiviral Research Mar 2019The potential protection of poly-ICLC (Hiltonol) a double stranded RNA (dsRNA) against EBOV infection was assessed with prophylactic and therapeutic administration to...
The potential protection of poly-ICLC (Hiltonol) a double stranded RNA (dsRNA) against EBOV infection was assessed with prophylactic and therapeutic administration to wild type and TLR3-negative mice, and in non-human primates (NHPs) by measuring EBOL serum titers, survival extension, and serum liver and kidney function markers. Various doses of aqueous and liposomal poly-ICLC monotherapy provided robust protection in otherwise lethal murine EBOV challenge models, when treatment is started on the day 0 or one day after virus challenge. There was no advantage of liposomal vs. the aqueous poly-ICLC form. Protection appeared to be independent of TLR-3. NHPs treated with poly-ICLC and challenged with EBOV survived longer but eventually succumbed to Ebola infection. Nevertheless, the liver and kidney serum markers were markedly reduced in the infected and treated NHPs. In the two longest surviving poly-ICLC- treated NHPs, the day 10 serum EBOV titer was reduced 2.1 and 30 fold respectively.
Topics: Animals; Carboxymethylcellulose Sodium; Democratic Republic of the Congo; Female; Hemorrhagic Fever, Ebola; Interferon Inducers; Macaca fascicularis; Mice; Mice, Inbred BALB C; Poly I-C; Polylysine
PubMed: 30611774
DOI: 10.1016/j.antiviral.2018.12.020 -
Cancer Immunology, Immunotherapy : CII Mar 2019Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat...
Vaccines consisting of synthetic peptides representing cytotoxic T-lymphocyte (CTL) epitopes have long been considered as a simple and cost-effective approach to treat cancer. However, the efficacy of these vaccines in the clinic in patients with measurable disease remains questionable. We believe that the poor performance of peptide vaccines is due to their inability to generate sufficiently large CTL responses that are required to have a positive impact against established tumors. Peptide vaccines to elicit CTLs in the clinic have routinely been administered in the same manner as vaccines designed to induce antibody responses: injected subcutaneously and in many instances using Freund's adjuvant. We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Furthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether peptide vaccines will ever work to treat cancer.
Topics: Administration, Intravenous; Animals; Cancer Vaccines; Injections, Subcutaneous; Mice; Mice, Inbred C57BL; T-Lymphocytes, Cytotoxic; Vaccination; Vaccines, Subunit
PubMed: 30604041
DOI: 10.1007/s00262-018-02294-5 -
Nature Jan 2019Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors. For treatments using...
Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential. There is limited intratumoural infiltration of immune cells in glioblastoma and these tumours contain only 30-50 non-synonymous mutations. Exploitation of the full repertoire of tumour antigens-that is, both unmutated antigens and neoepitopes-may offer more effective immunotherapies, especially for tumours with a low mutational load. Here, in the phase I trial GAPVAC-101 of the Glioma Actively Personalized Vaccine Consortium (GAPVAC), we integrated highly individualized vaccinations with both types of tumour antigens into standard care to optimally exploit the limited target space for patients with newly diagnosed glioblastoma. Fifteen patients with glioblastomas positive for human leukocyte antigen (HLA)-A*02:01 or HLA-A*24:02 were treated with a vaccine (APVAC1) derived from a premanufactured library of unmutated antigens followed by treatment with APVAC2, which preferentially targeted neoepitopes. Personalization was based on mutations and analyses of the transcriptomes and immunopeptidomes of the individual tumours. The GAPVAC approach was feasible and vaccines that had poly-ICLC (polyriboinosinic-polyribocytidylic acid-poly-L-lysine carboxymethylcellulose) and granulocyte-macrophage colony-stimulating factor as adjuvants displayed favourable safety and strong immunogenicity. Unmutated APVAC1 antigens elicited sustained responses of central memory CD8 T cells. APVAC2 induced predominantly CD4 T cell responses of T helper 1 type against predicted neoepitopes.
Topics: Adult; Aged; Antigens, Neoplasm; CD8-Positive T-Lymphocytes; Cancer Vaccines; Epitopes, T-Lymphocyte; Female; Glioblastoma; HLA-A Antigens; Humans; Immunologic Memory; Male; Middle Aged; Precision Medicine; T-Lymphocytes, Helper-Inducer; Treatment Outcome
PubMed: 30568303
DOI: 10.1038/s41586-018-0810-y