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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 -
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 -
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 -
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 -
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 -
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 -
Nature Cancer Dec 2020Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand... (Randomized Controlled Trial)
Randomized Controlled Trial
Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.
Topics: Cancer Vaccines; Dendritic Cells; Humans; Immunity; Melanoma; Membrane Proteins; fms-Like Tyrosine Kinase 3
PubMed: 35121932
DOI: 10.1038/s43018-020-00143-y -
Cancer Immunology, Immunotherapy : CII Nov 2021The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways,...
The nanoparticle complex of cholesteryl pullulan (CHP) and NY-ESO-1 antigen protein (CHP-NY-ESO-1) presents multiple epitope peptides to MHC class I and II pathways, leading to CD8 and CD4 T cell responses. Poly-ICLC is a synthetic, double-stranded RNA, an agonist of toll-like receptor (TLR)-3, and a cytoplasmic receptor of melanoma differentiation-associated gene (MDA)-5. It should be a suitable immune adjuvant of cancer vaccine to overcome the inhibitory tumor microenvironment. We conducted a phase 1 clinical trial of CHP-NY-ESO-1 with poly-ICLC in patients with advanced or recurrent esophageal cancer. CHP-NY-ESO-1/poly-ICLC (μg/mg) was administered at a dose of 200/0.5 or 200/1.0 (cohorts 1 and 2, respectively) every 2 weeks for a total of six doses. The primary endpoints were safety and immune response. The secondary endpoint was tumor response. In total, 16 patients were enrolled, and six patients in each cohort completed the trial. The most common adverse event (AE) was injection site skin reaction (86.7%). No grade 3 or higher drug-related AEs were observed. No tumor responses were observed, and three patients (30%) had stable disease. The immune response was comparable between the two cohorts, and all patients (100%) achieved antibody responses with a median of 2.5 vaccinations. Comparing CHP-NY-ESO-1 alone to the poly-ICLC combination, all patients in both groups exhibited antibody responses, but the titers were higher in the combination group. In a mouse model, adding anti-PD-1 antibody to the combination of CHP-NY-ESO-1/poly-ICLC suppressed the growth of NY-ESO-1-expressing tumors. Combining the vaccine with PD-1 blockade holds promise in human trials.
Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Animals; Antigens, Neoplasm; Cancer Vaccines; Carboxymethylcellulose Sodium; Esophageal Neoplasms; Female; Glucans; Humans; Interferon Inducers; Male; Membrane Proteins; Mice; Middle Aged; Nanoparticles; Poly I-C; Polylysine
PubMed: 33751208
DOI: 10.1007/s00262-021-02892-w -
Pharmacological Research Feb 2023The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose...
The efficacy of treatment for advanced hepatocellular carcinoma (HCC) has remained limited. Polyinosinic-polycytidylic acid-poly-L-lysine carboxymethylcellulose (poly-ICLC) is a synthetic double-stranded RNA that serves as a viral mimic and induces an immune response. Intratumoral (IT) poly-ICLC injections can induce an autovaccination effect and prime the immune system, whereas intramuscular (IM) injection of poly-ICLC can attract and maintain tumor-specific cytotoxic T lymphocytes in tumors. We found that IT injection of poly-ICLC upregulated the expression of CD83 and CD86 on conventional type 1 dendritic cells in tumors. Combination therapy with IT followed by IM injections of poly-ICLC significantly inhibited tumor growth and increased the tumor-infiltrating CD8 T cells in two syngeneic mouse models of HCC. Depletion of CD8 T cells attenuated the antitumor effect. An IFN-γ enzyme-linked immunospot of purified tumoral CD8 T cells revealed a significant proportion of tumor-specific T cells. Finally, the sequential poly-ICLC therapy induced abscopal effects in two dual-tumor models. This study provides evidence that the sequential poly-ICLC therapy significantly increased infiltration of tumor-specific CD8 T cells in the tumors and induced CD8 T cell-dependent inhibition of tumor growth, as well as abscopal effects.
Topics: Animals; Mice; Carcinoma, Hepatocellular; Carboxymethylcellulose Sodium; CD8-Positive T-Lymphocytes; Liver Neoplasms; Poly I-C; Polylysine; Vaccination
PubMed: 36621619
DOI: 10.1016/j.phrs.2023.106646 -
Cancer Immunology Research Jan 2020Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results... (Randomized Controlled Trial)
Randomized Controlled Trial
Given its ability to induce both humoral and cellular immune responses, NY-ESO-1 has been considered a suitable antigen for a cancer vaccine. Despite promising results from early-phase clinical studies in patients with melanoma, NY-ESO-1 vaccine immunotherapy has not been widely investigated in larger trials; consequently, many questions remain as to the optimal vaccine formulation, predictive biomarkers, and sequencing and timing of vaccines in melanoma treatment. We conducted an adjuvant phase I/II clinical trial in high-risk resected melanoma to optimize the delivery of poly-ICLC, a TLR-3/MDA-5 agonist, as a component of vaccine formulation. A phase I dose-escalation part was undertaken to identify the MTD of poly-ICLC administered in combination with NY-ESO-1 and montanide. This was followed by a randomized phase II part investigating the MTD of poly-ICLC with NY-ESO-1 with or without montanide. The vaccine regimens were generally well tolerated, with no treatment-related grade 3/4 adverse events. Both regimens induced integrated NY-ESO-1-specific CD4 T-cell and humoral responses. CD8 T-cell responses were mainly detected in patients receiving montanide. T-cell avidity toward NY-ESO-1 peptides was higher in patients vaccinated with montanide. In conclusion, NY-ESO-1 protein in combination with poly-ICLC is safe, well tolerated, and capable of inducing integrated antibody and CD4 T-cell responses in most patients. Combination with montanide enhances antigen-specific T-cell avidity and CD8 T-cell cross-priming in a fraction of patients, indicating that montanide contributes to the induction of specific CD8 T-cell responses to NY-ESO-1.
Topics: Adjuvants, Immunologic; Aged; Antigens, Neoplasm; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cancer Vaccines; Carboxymethylcellulose Sodium; Cross-Priming; Female; Humans; Immunity, Cellular; Immunity, Humoral; Interferon Inducers; Male; Mannitol; Melanoma; Membrane Proteins; Middle Aged; Oleic Acids; Patient Safety; Poly I-C; Polylysine; Skin Neoplasms; Treatment Outcome
PubMed: 31699709
DOI: 10.1158/2326-6066.CIR-19-0545