scholarly journals Nanoparticle delivery of immunostimulatory oligonucleotides enhances response to checkpoint inhibitor therapeutics

2020 ◽  
Vol 117 (24) ◽  
pp. 13428-13436 ◽  
Author(s):  
Colin G. Buss ◽  
Sangeeta N. Bhatia
Keyword(s):  
Animal Models ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Engineered Nanoparticles ◽  
Therapeutic Effects

The recent advent of immune checkpoint inhibitor (CPI) antibodies has revolutionized many aspects of cancer therapy, but the efficacy of these breakthrough therapeutics remains limited, as many patients fail to respond for reasons that still largely evade understanding. An array of studies in human patients and animal models has demonstrated that local signaling can generate strongly immunosuppressive microenvironments within tumors, and emerging evidence suggests that delivery of immunostimulatory molecules into tumors can have therapeutic effects. Nanoparticle formulations of these cargoes offer a promising way to maximize their delivery and to enhance the efficacy of checkpoint inhibitors. We developed a modular nanoparticle system capable of encapsulating an array of immunostimulatory oligonucleotides that, in some cases, greatly increase their potency to activate inflammatory signaling within immune cells in vitro. We hypothesized that these immunostimulatory nanoparticles could suppress tumor growth by activating similar signaling in vivo, and thereby also improve responsiveness to immune checkpoint inhibitor antibody therapies. We found that our engineered nanoparticles carrying a CpG DNA ligand of TLR9 can suppress tumor growth in several animal models of various cancers, resulting in an abscopal effect on distant tumors, and improving responsiveness to anti-CTLA4 treatment with combinatorial effects after intratumoral administration. Moreover, by incorporating tumor-homing peptides, immunostimulatory nucleotide-bearing nanoparticles facilitate antitumor efficacy after systemic intravenous (i.v.) administration.

scholarly journals Adaptive Antitumor Immune Response Stimulated by Bio-nanoparticle Based Vaccine and Checkpoint Blockade

2021 ◽  
Author(s):  
Xuewei Bai ◽  
Yanmei Zhou ◽  
Yuki Yokota ◽  
Yoshihiro Matsumoto ◽  
Bo Zhai ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Adaptive Immune Response ◽  
Control Group ◽  
Lymphoid Structures

Abstract Background: Interactions between tumor and microenvironment determines the response to immunotherapy. Triple negative breast cancer (TNBC) and hepatocellular carcinoma (HCC) have exhibited suboptimal responses to immune checkpoint inhibitors. Aspartate beta-hydroxylase (ASPH), an oncofetal protein and tumor associated antigen (TAA), is a potential target for immunotherapy. Methods: Orthotopic TNBC and subcutaneous HCC murine models were established. Immunohistochemistry, flow cytometry, ELISA and in vitro cytotoxicity assays were performed. Results: The ASPH-MYC signaling cascade upregulates PD-L1 expression on breast and liver tumor cells. A bio-nanoparticle based vaccine targeting ASPH was administrated to BALB/c mice harboring syngeneic HCC or TNBC tumors, either alone or in combination with PD-1 blockade. In the control group, autocrine CXCL13-CXCR5 axis promoted cancer development and progression. Inhibition between PD-L1+ cancer cells and PD-1+ T cells resulted in T cell exhaustion and apoptosis. In contrast, combination therapy significantly suppressed primary hepatic or mammary tumor growth with distant pulmonary metastases in TNBC. An adaptive immune response was attributed to expansion of activated CD4+ Th1/CD8+ CTLs with enhanced effector function and high titers of ASPH-specific antibody. When the PD-1/PD-L1 signal was inhibited, CXCL13 produced by ASPH+ cancer cells recruited CXCR5+/CD8+ T lymphocytes to tertiary lymphoid structures (TLSs), which secreted CXCL13 to recruit more CXCR5+ immune cells and to lyse CXCR5+ cancer cells. Upon combination treatment, the presence of TLSs predicts sensitivity to immune checkpoint inhibitor blockade. Conclusions: Synergistic antitumor efficacy attributable to a λ phage vaccine specifically targeting ASPH combined with an immune checkpoint inhibitor represents a new approach for TNBC and HCC.

scholarly journals Therapeutic Effects of a Neoantigen Vaccine With an Immune Checkpoint Inhibitor in a Cisplatin-Treated Mouse Model

2021 ◽  
Author(s):  
Sung Eun Lee ◽  
Gun-Young Jang ◽  
Ji Won Lee ◽  
Hee Dong Han ◽  
Yeong-Min Park ◽  
...  
Keyword(s):  
Immune System ◽  
T Cell ◽  
Tumor Growth ◽  
Mouse Models ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Treated Mouse ◽  
Therapeutic Effects ◽  
Cluster Of Differentiation

Abstract Background: Cancer immunotherapy is widely used as a treatment for cancer that works by improving the immune system with fewer side effects than conventional methods. Neoantigen vaccines are one form of immunotherapy that use cancer-specific neoantigens that are extracted from cancer patients and are not recognized by normal cells in the immune system.Methods: In this study, mutant genes of 4T1 mouse breast cancer cells were identified by direct sequence analysis using tumor-specific MHC I (Major Histocompatibility Complex) or MHC II epitopes through in vivo experiments. Results: The neoantigen vaccine with mutant CD4+ or CD8+ T cell-reactive neoantigen peptides was shown to inhibit tumor growth, increase long-term survival, and induce the secretion of IFN-γ (Interferon gamma) in the cisplatin-treated mouse models. In particular, mutant CD4+ T cell neoantigen peptides induced full potential anti-tumor effects, whereas dual treatment with CD4+ (Cluster of differentiation 4) and CD8+ (Cluster of differentiation 8) T cell neoantigen peptides increased the suppression of tumor growth. Moreover, the combination of neoantigen vaccine with mutant CD4+ T cell neoantigen peptide and anti-PD-L1 (Programmed death-ligand 1) as an immune checkpoint inhibitor (ICI) has been shown to have synergistic therapeutic effects in cisplatin-treated mouse models. Conclusion: This study, therefore, proved that cancer cell-derived neoantigens have great potential to induce immunogenic responses and cancer treatment effects, along with synergistic efficiency when applied to various combinational therapies. Through the methods that were used in our experiments, we could contribute to the development of new adjuvants for evaluating efficacy, discovering unfound neoantigens, and investigating immune checkpoint blockade antibodies for non-clinical studies.

scholarly journals A Small Molecule Antagonist of PD-1/PD-L1 Interactions Acts as an Immune Checkpoint Inhibitor for NSCLC and Melanoma Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yuanyuan Wang ◽  
Tingxuan Gu ◽  
Xueli Tian ◽  
Wenwen Li ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Monoclonal Antibodies ◽  
Small Molecule ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Small Molecule Antagonist ◽  
Programmed Death

Immune checkpoint inhibitors, such as monoclonal antibodies targeting programmed death 1 (PD-1) and programmed death ligand-1 (PD-L1), have achieved enormous success in the treatment of several cancers. However, monoclonal antibodies are expensive to produce, have poor tumor penetration, and may induce autoimmune side effects, all of which limit their application. Here, we demonstrate that PDI-1 (also name PD1/PD-L1 inhibitor 1), a small molecule antagonist of PD-1/PD-L1 interactions, shows potent anti-tumor activity in vitro and in vivo and acts by relieving PD-1/PD-L1-induced T cell exhaustion. We show that PDI-1 binds with high affinity to purified human and mouse PD-1 and PD-L1 proteins and is a competitive inhibitor of human PD-1/PD-L1 binding in vitro. Incubation of ex vivo activated human T cells with PDI-1 enhanced their cytotoxicity towards human lung cancer and melanoma cells, and concomitantly increased the production of granzyme B, perforin, and inflammatory cytokines. Luciferase reporter assays showed that PDI-1 directly increases TCR-mediated activation of NFAT in a PD-1/PD-L1-dependent manner. In two syngeneic mouse tumor models, the intraperitoneal administration of PDI-1 reduced the growth of tumors derived from human PD-L1-transfected mouse lung cancer and melanoma cells; increased and decreased the abundance of tumor-infiltrating CD8+ and FoxP3+ CD4+ T cells, respectively; decreased the abundance of PD-L1-expressing tumor cells, and increased the production of inflammatory cytokines. The anti-tumor effect of PDI-1 in vivo was comparable to that of the anti-PD-L1 antibody atezolizumab. These results suggest that the small molecule inhibitors of PD-1/PD-L1 may be effective as an alternative or complementary immune checkpoint inhibitor to monoclonal antibodies.

scholarly journals Targeted Alpha-Particle Radiotherapy and Immune Checkpoint Inhibitors Induces Cooperative Inhibition on Tumor Growth of Malignant Melanoma

Cancers ◽  
2021 ◽  
Vol 13 (15) ◽  
pp. 3676
Author(s):  
Mengshi Li ◽  
Dijie Liu ◽  
Dongyoul Lee ◽  
Yinwen Cheng ◽  
Nicholas J. Baumhover ◽  
...  
Keyword(s):  
Cell Death ◽  
Tumor Growth ◽  
Immune Checkpoint ◽  
Radionuclide Therapy ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
The Body ◽  
Immune Recognition

Radiotherapy can facilitate the immune recognition of immunologically “cold” tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically “cold” tumors throughout the body responsive to ICIs and immunologically “hot”. Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

scholarly journals Phytochemicals in Cancer Immune Checkpoint Inhibitor Therapy

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1107
Author(s):  
Juwon Lee ◽  
Youngjin Han ◽  
Wenyu Wang ◽  
HyunA Jo ◽  
Heeyeon Kim ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Therapeutic Option ◽  
In Vitro Models ◽  
Immune Checkpoints ◽  
Checkpoint Inhibitor Therapy ◽  
Cancer Types

The interaction of immune checkpoint molecules in the tumor microenvironment reduces the anti-tumor immune response by suppressing the recognition of T cells to tumor cells. Immune checkpoint inhibitor (ICI) therapy is emerging as a promising therapeutic option for cancer treatment. However, modulating the immune system with ICIs still faces obstacles with severe immunogenic side effects and a lack of response against many cancer types. Plant-derived natural compounds offer regulation on various signaling cascades and have been applied for the treatment of multiple diseases, including cancer. Accumulated evidence provides the possibility of efficacy of phytochemicals in combinational with other therapeutic agents of ICIs, effectively modulating immune checkpoint-related signaling molecules. Recently, several phytochemicals have been reported to show the modulatory effects of immune checkpoints in various cancers in in vivo or in vitro models. This review summarizes druggable immune checkpoints and their regulatory factors. In addition, phytochemicals that are capable of suppressing PD-1/PD-L1 binding, the best-studied target of ICI therapy, were comprehensively summarized and classified according to chemical structure subgroups. It may help extend further research on phytochemicals as candidates of combinational adjuvants. Future clinical trials may validate the synergetic effects of preclinically investigated phytochemicals with ICI therapy.

scholarly journals BTK Inhibition Reverses MDSC-Mediated Immunosuppression and Enhances Response to Anti-PDL1 Therapy in Neuroblastoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 817
Author(s):  
Mehreen Ishfaq ◽  
Timothy Pham ◽  
Cooper Beaman ◽  
Pablo Tamayo ◽  
Alice L. Yu ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Growth ◽  
Checkpoint Inhibitors ◽  
No Production ◽  
Free Survival ◽  
T Cell Infiltration ◽  
Car T ◽  
Checkpoint Inhibitor Therapy

MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers, including NB. Ibrutinib, an irreversible molecular inhibitor of BTK, has been widely studied in B cell malignancies, and recently, this drug is repurposed for the treatment of solid tumors. Herein we report that BTK is highly expressed in both granulocytic and monocytic murine MDSCs isolated from mice bearing NB tumors, and its increased expression correlates with a poor relapse-free survival probability of NB patients. Moreover, in vitro treatment of murine MDSCs with ibrutinib altered NO production, decreased mRNA expression of Ido, Arg, Tgfβ, and displayed defects in T-cell suppression. Consistent with these findings, in vivo inhibition of BTK with ibrutinib resulted in reduced MDSC-mediated immune suppression, increased CD8+ T cell infiltration, decreased tumor growth, and improved response to anti-PDL1 checkpoint inhibitor therapy in a murine model of NB. These results demonstrate that ibrutinib modulates immunosuppressive functions of MDSC and can be used either alone or in combination with immunotherapy for augmenting antitumor immune responses in NB.

376 A phase I/II study of live biotherapeutic MRx0518 in combination with pembrolizumab in patients refractory to immune checkpoint inhibitors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A401-A401
Author(s):  
Shubham Pant ◽  
Amishi Shah ◽  
Pavlos Msaouel ◽  
Matthew Campbell ◽  
Shi-Ming Tu ◽  
...  
Keyword(s):  
Phase I ◽  
Disease Progression ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Tumour Response ◽  
Checkpoint Inhibition ◽  
Single Strain

BackgroundMRx0518 is a novel, human gut microbiome-derived, single-strain, oral live biotherapeutic. It is a bacterium of the Enterococcus genus that was selected for development in the treatment of solid tumours for its strong in vitro and in vivo immunostimulatory activity. In vivo studies have shown that MRx0518 can inhibit tumour growth in different syngeneic cancer models as monotherapy and in combination with checkpoint inhibitors. MRx0518 has been shown to reduce Treg and increase Th1 and Tc1 lymphocyte differentiation in vitro, and increase intratumoral CD4+ and CD8+ T cells and NK cells in vivo.This phase I/II clinical study is evaluating the combination of MRx0518 and pembrolizumab in a cohort of heavily pre-treated patients refractory to immune checkpoint inhibitors (ICIs) to assess whether it is safe and can provide a clinical benefit.MethodsThe study is being conducted in two parts. Part A is complete and evaluated safety of the combination therapy in a cohort of 12 mRCC and mNSCLC patients. This data was assessed by the Safety Review Committee and it was determined appropriate to proceed to Part B. Part B is now recruiting up to 30 additional patients per indication (RCC, NSCLC or bladder cancer) at several US sites. Patients in both parts must be refractory to checkpoint inhibition. This is defined as having had an initial benefit from PD-1 pathway targeting immune checkpoint inhibition (ICI) but developing disease progression confirmed by two radiological scans ≥4 weeks apart in the absence of rapid clinical progression and within 12 weeks of last dose of ICI. Patients are treated with 1 capsule of MRx0518 (1 × 1010 to 1 × 1011 CFU) twice daily and pembrolizumab (200 mg every 3 weeks) for up to 35 cycles or until disease progression. Tumour response is assessed every 9 weeks per RECIST. Blood, stool and urine samples are collected throughout the study to evaluate immune markers and microbiome. Patients may choose to consent to tissue biopsies. The primary objective of the study is to evaluate safety of the combination by monitoring toxicities in the first cycle of treatment. Secondary objectives are to evaluate efficacy via ORR, DOR, DCR (CR, PR or SD ≥6 months) and PFS. Exploratory objectives are to evaluate biomarkers of treatment effect, impact on microbiota and OS and correlation of clinical outcome with PD-L1 CPS/TPS.ResultsN/AConclusionsN/ATrial RegistrationNCT03637803Ethics ApprovalThis study was approved by University of Texas MD Anderson’s Institutional Review Board; approval ref. 2018-0290

The emerging use of immune checkpoint blockade in the adjuvant setting for solid tumors: a review

Immunotherapy ◽  
2019 ◽  
Vol 11 (16) ◽  
pp. 1409-1422 ◽  
Author(s):  
Elissar Moujaess ◽  
Fady Gh Haddad ◽  
Roland Eid ◽  
Hampig Raphael Kourie
Keyword(s):  
Solid Tumors ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Adjuvant Setting ◽  
Lung Cancers ◽  
Metastatic Setting ◽  
Postoperative Setting

The use of immune checkpoint inhibitors has been approved in the advanced and metastatic setting for many types of solid tumors. Nonetheless, their role in the adjuvant setting is limited to the treatment of surgically resected melanoma. Ipilimumab was the first immune checkpoint inhibitor approved for this indication, followed by nivolumab and pembrolizumab. Many ongoing trials are evaluating these molecules in the postoperative setting, alone or in combination with other therapies. Preliminary results are promising regarding the treatment of other cutaneous tumors, lung cancers, head and neck squamous cell carcinomas, bladder cancer and renal cell carcinomas. Some data assessing their use for the adjuvant treatment of esophageal, colorectal, ovarian cancer and other solid tumors are similarly emerging.

scholarly journals Enterococcus peptidoglycan remodeling promotes immune checkpoint inhibitor therapy

2020 ◽  
Author(s):  
Matthew E. Griffin ◽  
Juliel Espinosa ◽  
Jessica L. Becker ◽  
Jyoti K. Jha ◽  
Gary R. Fanger ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Immune Checkpoint ◽  
Molecular Mechanisms ◽  
Immune Checkpoint Inhibitor ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Mouse Tumor ◽  
Peptidoglycan Hydrolases ◽  
Checkpoint Inhibitor Therapy ◽  
Specific Species

AbstractThe antitumor efficacy of cancer immunotherapy has been correlated with specific species within the gut microbiota. However, molecular mechanisms by which these microbes affect host response to immunotherapy remain elusive. Here we show that specific members of the bacterial genus Enterococcus can promote anti-PD-L1 immunotherapy in mouse tumor models. The active enterococci express and secrete orthologs of the NlpC/p60 peptidoglycan hydrolase SagA that generate immune-active muropeptides. Expression of SagA in non-protective E. faecalis was sufficient to promote antitumor activity of clinically approved checkpoint targets, and its activity required the peptidoglycan sensor Nod2. Notably, SagA-engineered probiotics or synthetic muropeptides also promoted checkpoint inhibitor antitumor activity. Our data suggest that microbiota species with unique peptidoglycan remodeling activity may enhance immunotherapy and could be leveraged for next-generation adjuvants.One Sentence SummaryA conserved family of secreted NlpC/p60 peptidoglycan hydrolases from Enterococcus promote antitumor activity of immune checkpoint inhibitors.

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