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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 -
The Urologic Clinics of North America Nov 2020Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and... (Review)
Review
Relatively simple, synthetic, double-stranded RNAs can be powerful viral pathogen-associated molecular pattern (PAMP) mimics, inducing a panoply of antiviral and antitumor responses that act at multiple stages of host defense. Their mechanisms of action and uses are beginning to be understood, alone, in combination with other therapeutics, or as novel PAMP-adjuvants providing the critical danger signal that has been missing from most cancer and other modern vaccines. Dose, timing, route of administration combinations, and other clinical variables can have a critical impact on immunogenicity. This article reviews advances in the use of polyinosinic-polycytidylic acid and derivatives, in particular poly-ICLC.
Topics: Adjuvants, Immunologic; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Humans; Immunologic Factors; Male; Pathogen-Associated Molecular Pattern Molecules; Poly I-C; Polylysine; Prostatic Neoplasms; RNA, Double-Stranded
PubMed: 33446322
DOI: 10.1016/j.ucl.2020.10.003 -
Journal of Experimental & Clinical... Jun 2021Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological... (Review)
Review
Immunotherapy is currently under intensive investigation as a potential breakthrough treatment option for glioblastoma. Given the anatomical and immunological complexities surrounding glioblastoma, lymphocytes that infiltrate the brain to develop durable immunity with memory will be key. Polyinosinic:polycytidylic acid, or poly(I:C), and its derivative poly-ICLC could serve as a priming or boosting therapy to unleash lymphocytes and other factors in the (immuno)therapeutic armory against glioblastoma. Here, we present a systematic review on the effects and efficacy of poly(I:C)/poly-ICLC for glioblastoma treatment, ranging from preclinical work on cellular and murine glioblastoma models to reported and ongoing clinical studies. MEDLINE was searched until 15 May 2021 to identify preclinical (glioblastoma cells, murine models) and clinical studies that investigated poly(I:C) or poly-ICLC in glioblastoma. A systematic review approach was conducted according to PRISMA guidelines. ClinicalTrials.gov was queried for ongoing clinical studies. Direct pro-tumorigenic effects of poly(I:C) on glioblastoma cells have not been described. On the contrary, poly(I:C) changes the immunological profile of glioblastoma cells and can also kill them directly. In murine glioblastoma models, poly(I:C) has shown therapeutic relevance as an adjuvant therapy to several treatment modalities, including vaccination and immune checkpoint blockade. Clinically, mostly as an adjuvant to dendritic cell or peptide vaccines, poly-ICLC has been demonstrated to be safe and capable of eliciting immunological activity to boost therapeutic responses. Poly-ICLC could be a valuable tool to enhance immunotherapeutic approaches for glioblastoma. We conclude by proposing several promising combination strategies that might advance glioblastoma immunotherapy and discuss key pre-clinical aspects to improve clinical translation.
Topics: Animals; Brain Neoplasms; Cancer Vaccines; Carboxymethylcellulose Sodium; Clinical Trials as Topic; Glioblastoma; Humans; Immune Checkpoint Inhibitors; Immunotherapy; Mice; Poly I-C; Polylysine
PubMed: 34172082
DOI: 10.1186/s13046-021-02017-2 -
Seminars in Immunology Jun 2020Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low... (Review)
Review
Immunotherapies have become the first line of treatment for many cancer types. Unfortunately, only a small fraction of patients benefits from these therapies. This low rate of success can be attributed to 3 main barriers: 1) low frequency of anti-tumor specific T cells; 2) lack of infiltration of the anti-tumor specific T cells into the tumor parenchyma and 3) accumulation of highly suppressive cells in the tumor mass that inhibit the effector function of the anti-tumor specific T cells. Thus, the identification of immunomodulators that can increase the frequency and/or the infiltration of antitumor specific T cells while reducing the suppressive capacity of the tumor microenvironment is necessary to ensure the effectiveness of T cell immunotherapies. In this review, we discuss the potential of poly-ICLC as a multi-functional immune modulator for treating cancer and its impact on the 3 above mentioned barriers. We describe the unique capacity of poly-ICLC in stimulating 2 separate pattern recognition receptors, TLR3 and cytosolic MDA5 and the consequences of these activations on cytokines and chemokines production. We emphasize the role of poly-ICLC as an adjuvant in the setting of peptide-based cancer vaccines and in situ tumor vaccination by mimicking natural immune responses to infections. Finally, we summarize the impact of poly-ICLC in enhancing T infiltration into the tumor parenchyma and address the implication of this finding in the clinic.
Topics: Animals; Antineoplastic Agents; Carboxymethylcellulose Sodium; Cytokines; Humans; Immunity, Innate; Immunologic Factors; Immunomodulation; Interferon-Induced Helicase, IFIH1; Lymphocytes, Tumor-Infiltrating; Neoplasms; Poly I-C; Polylysine; Receptors, Pattern Recognition; Toll-Like Receptor 3
PubMed: 33011064
DOI: 10.1016/j.smim.2020.101414 -
Cancer Letters Jun 2023Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive...
Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8 T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8 T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Liver Neoplasms; CD8-Positive T-Lymphocytes; Mice, Inbred C57BL; Cancer Vaccines
PubMed: 37088327
DOI: 10.1016/j.canlet.2023.216192 -
Expert Review of Vaccines Mar 2015Pathogen-associated molecular patterns (PAMPs) are stand-alone immunomodulators or 'danger signals,' that are increasingly recognized as critical components of many... (Review)
Review
Pathogen-associated molecular patterns (PAMPs) are stand-alone immunomodulators or 'danger signals,' that are increasingly recognized as critical components of many modern vaccines. Polyinosinic-polycytidylic acid (poly-IC) is a synthetic dsRNA that can activate multiple elements of the host defense in a pattern that parallels that of a viral infection. When properly combined with an antigen, it can be utilized as a PAMP-adjuvant, resulting in modulation and optimization of the antigen-specific immune response. We briefly review the preclinical and clinical uses of poly-IC and two poly-IC derivatives, poly-IC12U (Ampligen) and poly-ICLC (Hiltonol), as vaccine adjuvants.
Topics: Adjuvants, Immunologic; Humans; Poly I-C; Vaccines
PubMed: 25308798
DOI: 10.1586/14760584.2015.966085 -
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 -
Cancers May 2021Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded viral RNA analog widely tested as a component of human...
Polyinosinic-polycytidylic acid-poly-l-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded viral RNA analog widely tested as a component of human therapeutic cancer vaccines and as a standalone agent for treating human cancers. However, there are no reports on the use of poly-ICLC for treating canine cancers. This study aimed to investigate the clinical efficacy, quality of life (QL), and adverse events of poly-ICLC treatment in dogs with advanced cancers. The treatment protocol consisted of weekly intratumoral doses of poly-ICLC. The canine patients underwent clinical, laboratory, and imaging tests, and their owners answered weekly QL questionnaires. Fourteen canine patients with different types of spontaneous advanced tumors were enrolled. Most dogs had received prior conventional therapies. Five dogs received at least 12 doses of poly-ICLC: the injected tumor was stable in three dogs, there was a partial response in one, and the injected tumor significantly enlarged in the other. The QL scoring remained stable or increased in most cases. Mild adverse events related to poly-ICLC were observed in 10 of the 14 patients. The data showed that intratumoral poly-ICLC therapy was well tolerated in dogs with advanced cancers, with clinical benefit and improved QL scores observed in some dogs.
PubMed: 34066908
DOI: 10.3390/cancers13092237 -
Annals of Oncology : Official Journal... May 2018Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated... (Clinical Trial)
Clinical Trial
BACKGROUND
Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects.
PATIENTS AND METHODS
In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing.
RESULTS
Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD.
CONCLUSIONS
This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.
Topics: Adult; Aged; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; Combined Modality Therapy; Cyclophosphamide; Cytokines; Dendritic Cells; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Injections, Intralesional; Leukocytes, Mononuclear; Male; Middle Aged; Neoplasms; Poly I-C; Polylysine; Radiosurgery; Response Evaluation Criteria in Solid Tumors
PubMed: 29554212
DOI: 10.1093/annonc/mdy089 -
Journal For Immunotherapy of Cancer Jun 2021While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based...
BACKGROUND
While adoptive transfer of T-cells has been a major medical breakthrough for patients with B cell malignancies, the development of safe and effective T-cell-based immunotherapy for central nervous system (CNS) tumors, such as glioblastoma (GBM), still needs to overcome multiple challenges, including effective homing and persistence of T-cells. Based on previous observations that interleukin (IL)-17-producing T-cells can traffic to the CNS in autoimmune conditions, we evaluated CD8 T-cells that produce IL-17 and interferon-γ (IFN-γ) (Tc17-1) cells in a preclinical GBM model.
METHODS
We differentiated Pmel-1 CD8 T-cells into Tc17-1 cells and compared their phenotypic and functional characteristics with those of IFN-γ-producing CD8 T (Tc1) and IL-17-producing CD8 T (Tc17) cells. We also evaluated the therapeutic efficacy, persistence, and tumor-homing of Tc17-1 cells in comparison to Tc1 cells using a mouse GL261 glioma model.
RESULTS
In vitro, Tc17-1 cells demonstrated profiles of both Tc1 and Tc17 cells, including production of both IFN-γ and IL-17, although Tc17-1 cells demonstrated lesser degrees of antigen-specific cytotoxic activity compared with Tc1 cells. In mice-bearing intracranial GL261-Quad tumor and treated with temozolomide, Tc1 cells, but not Tc17-1, showed a significant prolongation of survival. However, when the T-cell transfer was combined with poly-ICLC and Pmel-1 peptide vaccine, both Tc1 and Tc17-1 cells exhibited significantly prolonged survival associated with upregulation of very late activation antigen-4 on Tc17-1 cells in vivo. Glioma cells that recurred following the therapy lost the susceptibility to Pmel-1-derived cytotoxic T-cells, indicating that immuno-editing was a mechanism of the acquired resistance.
CONCLUSIONS
Tc17-1 cells were equally effective as Tc1 cells when combined with poly-ICLC and peptide vaccine treatment.
Topics: CD8-Positive T-Lymphocytes; Carboxymethylcellulose Sodium; Glioma; Humans; Interferon-gamma; Interleukin-17; Poly I-C; Polylysine; Vaccines, Subunit
PubMed: 34193567
DOI: 10.1136/jitc-2021-002426