scholarly journals Perspective on a Modified Developmental and Reproductive Toxicity Testing Strategy for Cancer Immunotherapy

2016 ◽  
Vol 35 (3) ◽  
pp. 263-273 ◽  
Author(s):  
Rodney A. Prell ◽  
Wendy G. Halpern ◽  
Gautham K. Rao
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Reproductive Risk ◽  
Cell Responses ◽  
Maternal Immune System ◽  
Cancer Immunotherapeutic ◽  
Different Strains

The intent of cancer immunotherapy (CIT) is to generate and enhance T-cell responses against tumors. The tumor microenvironment establishes several inhibitory pathways that lead to suppression of the local immune response, which is permissive for tumor growth. The efficacy of different CITs, alone and in combination, stems from reinvigorating the tumor immune response via several mechanisms, including costimulatory agonists, checkpoint inhibitors, and vaccines. However, immune responses to other antigens (self and foreign) may also be enhanced, resulting in potentially undesired effects. In outbred mammalian pregnancies, the fetus expresses paternally derived alloantigens that are recognized as foreign by the maternal immune system. If unchecked or enhanced, maternal immunity to these alloantigens represents a developmental and reproductive risk and thus is a general liability for cancer immunotherapeutic molecules. We propose a tiered approach to confirm this mechanistic reproductive liability for CIT molecules. A rodent allopregnancy model is based on breeding 2 different strains of mice so that paternally derived alloantigens are expressed by the fetus. When tested with a cross-reactive biotherapeutic, small molecule drug, or surrogate molecule, this model should reveal on-target reproductive liabilities if the pathway is involved in maintaining pregnancy. Alternatively, allopregnancy models with genetically modified mice can be interrogated for exquisitely specific biotherapeutics with restricted species reactivity. The allopregnancy model represents a relatively straightforward approach to confirm an expected on-target reproductive risk for CIT molecules. For biotherapeutics, it could potentially replace more complex developmental and reproductive toxicity testing in nonhuman primates when a pregnancy hazard is confirmed or expected.

scholarly journals Design and Encapsulation of Immunomodulators onto Gold Nanoparticles in Cancer Immunotherapy

2021 ◽  
Vol 22 (15) ◽  
pp. 8037
Author(s):  
Akshita Chauhan ◽  
Tabassum Khan ◽  
Abdelwahab Omri
Keyword(s):  
Immune System ◽  
Immune Responses ◽  
Cancer Immunotherapy ◽  
Cytotoxic T Lymphocytes ◽  
Recent Progress ◽  
Checkpoint Inhibitors ◽  
Drug Clearance ◽  
Cell Permeability ◽  
Plasmonic Effect ◽  
Cancer Immunotherapeutic

The aim of cancer immunotherapy is to reactivate autoimmune responses to combat cancer cells. To stimulate the immune system, immunomodulators, such as adjuvants, cytokines, vaccines, and checkpoint inhibitors, are extensively designed and studied. Immunomodulators have several drawbacks, such as drug instability, limited half-life, rapid drug clearance, and uncontrolled immune responses when used directly in cancer immunotherapy. Several strategies have been used to overcome these limitations. A simple and effective approach is the loading of immunomodulators onto gold-based nanoparticles (GNPs). As gold is highly biocompatible, GNPs can be administered intravenously, which aids in increasing cancer cell permeability and retention time. Various gold nanoplatforms, including nanospheres, nanoshells, nanorods, nanocages, and nanostars have been effectively used in cancer immunotherapy. Gold nanostars (GNS) are one of the most promising GNP platforms because of their unusual star-shaped geometry, which significantly increases light absorption and provides high photon-to-heat conversion efficiency due to the plasmonic effect. As a result, GNPs are a useful vehicle for delivering antigens and adjuvants that support the immune system in killing tumor cells by facilitating or activating cytotoxic T lymphocytes. This review represents recent progress in encapsulating immunomodulators into GNPs for utility in a cancer immunotherapeutic regimen.

scholarly journals The Mechanism of Stimulating and Mobilizing the Immune System Enhancing the Anti-Tumor Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhengguo Wu ◽  
Shang Li ◽  
Xiao Zhu
Keyword(s):  
Immune Response ◽  
Immune System ◽  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Tumor Immunity ◽  
Checkpoint Inhibitors ◽  
The Body ◽  
Research Progress ◽  
Effective Population ◽  
Cell Components

Cancer immunotherapy is a kind of therapy that can control and eliminate tumors by restarting and maintaining the tumor-immune cycle and restoring the body’s normal anti-tumor immune response. Although immunotherapy has great potential, it is currently only applicable to patients with certain types of tumors, such as melanoma, lung cancer, and cancer with high mutation load and microsatellite instability, and even in these types of tumors, immunotherapy is not effective for all patients. In order to enhance the effectiveness of tumor immunotherapy, this article reviews the research progress of tumor microenvironment immunotherapy, and studies the mechanism of stimulating and mobilizing immune system to enhance anti-tumor immunity. In this review, we focused on immunotherapy against tumor microenvironment (TME) and discussed the important research progress. TME is the environment for the survival and development of tumor cells, which is composed of cell components and non-cell components; immunotherapy for TME by stimulating or mobilizing the immune system of the body, enhancing the anti-tumor immunity. The checkpoint inhibitors can effectively block the inhibitory immunoregulation, indirectly strengthen the anti-tumor immune response and improve the effect of immunotherapy. We also found the checkpoint inhibitors have brought great changes to the treatment model of advanced tumors, but the clinical treatment results show great individual differences. Based on the close attention to the future development trend of immunotherapy, this study summarized the latest progress of immunotherapy and pointed out a new direction. To study the mechanism of stimulating and mobilizing the immune system to enhance anti-tumor immunity can provide new opportunities for cancer treatment, expand the clinical application scope and effective population of cancer immunotherapy, and improve the survival rate of cancer patients.

scholarly journals Infections due to dysregulated immunity: an emerging complication of cancer immunotherapy

Thorax ◽  
2021 ◽  
pp. thoraxjnl-2021-217260
Author(s):  
Tommaso Morelli ◽  
Kohei Fujita ◽  
Gil Redelman-Sidi ◽  
Paul T Elkington
Keyword(s):  
Immune Response ◽  
Adverse Events ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immunosuppressive Treatment ◽  
Common Side Effect ◽  
Inflammatory Immune Response ◽  
New Framework

Immune checkpoint inhibitors (ICIs) have revolutionised cancer treatment. However, immune-related adverse events (irAEs) are a common side effect which can mimic infection. Additionally, treatment of irAEs with corticosteroids and other immunosuppressant agents can lead to opportunistic infection, which we have classed as immunotherapy infections due to immunosuppression. However, emerging reports demonstrate that some infections can be precipitated by ICIs in the absence of immunosuppressive treatment, in contrast to the majority of reported cases. These infections are characterised by a dysregulated inflammatory immune response, and so we propose they are described as immunotherapy infections due to dysregulated immunity. This review summarises the rapidly emerging evidence of these phenomena and proposes a new framework for considering infection in the context of cancer immunotherapy.

scholarly journals The Crosstalk between Microbiome and Immune Response in Gastric Cancer

2020 ◽  
Vol 21 (18) ◽  
pp. 6586
Author(s):  
Rihab Nasr ◽  
Ali Shamseddine ◽  
Deborah Mukherji ◽  
Farah Nassar ◽  
Sally Temraz
Keyword(s):  
Gastric Cancer ◽  
Immune Response ◽  
Gut Microbiome ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
Cell Responses ◽  
Host Epithelium ◽  
H Pylori

Gastric cancer is the end result of a complex interplay between host genetics, environmental factors, and microbial factors. The link between gut microbiome and gastric cancer has been attributed to persistent activation of the host’s immune system by gut microbiota. The end result of this dysregulated interaction between host epithelium and microbes is a state of chronic inflammation. Gut bacteria can promote anti-tumor immune responses through several mechanisms. These include triggering T-cell responses to bacterial antigens that can cross-react with tumor antigens or cause tumor-specific antigen recognition; engagement of pattern recognition receptors that mediate pro-immune or anti-inflammatory effects or via small metabolites that mediate systemic effects on the host. Here we review the role of the gut microbiome including H. pylori and non-H. pylori gastric bacteria, the immune response, and immunotherapy using checkpoint inhibitors. We also review the evidence for cross talk between the gut microbiome and immune response in gastric cancer.

scholarly journals Case Report: Adequate T and B Cell Responses in a SARS-CoV-2 Infected Patient After Immune Checkpoint Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
K. de Joode ◽  
A. A. M. Oostvogels ◽  
C. H. GeurtsvanKessel ◽  
R. D. de Vries ◽  
R. H. J. Mathijssen ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cell ◽  
Immune Checkpoint ◽  
Infected Patient ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Oncological Treatment ◽  
Cell Responses ◽  
B Cell Responses

After the COVID-19 outbreak, non-evidence based guidelines were published to advise clinicians on the adjustment of oncological treatment during this pandemic. As immune checkpoint inhibitors directly affect the immune system, concerns have arisen about the safety of immunotherapy during this pandemic. However, data on the immune response in oncology patients treated with immunotherapy are still lacking. Here, we present the adaptive immune response in a SARS-CoV-2 infected patient who was treated with immune checkpoint inhibitors for advanced renal cell cancer. To evaluate the immune response in this patient, the number of T cells and their major subsets were measured according to expression of markers for co-signalling, maturation, and chemotaxis at baseline, during therapy, and during the SARS-CoV-2 infection. In addition, plasma samples were analyzed for IgM and IgG antibodies and the ability of these antibodies to neutralise SARS-CoV-2. Despite several risk factors for an impaired immune response to SARS-CoV-2, both T- and B-cell responses were observed. Moreover, after treatment with immune checkpoint inhibitors, a sufficient cellular and humoral immune response was achieved in this SARS-CoV-2 infected patient. These findings warrant renewed discussion on withholding of immune checkpoint inhibitors during an ongoing COVID-19 pandemic.

scholarly journals Oncolytic Adenovirus: Prospects for Cancer Immunotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Yaqi Zhao ◽  
Zheming Liu ◽  
Lan Li ◽  
Jie Wu ◽  
Huibo Zhang ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Oncolytic Adenovirus ◽  
Oncolytic Viruses ◽  
Engineering Technology ◽  
Antiviral Immune Response ◽  
Oncolytic Adenoviruses ◽  
Genetic Engineering Technology ◽  
Oncologic Treatment

Immunotherapy has moved to the forefront of modern oncologic treatment in the past few decades. Various forms of immunotherapy currently are emerging, including oncolytic viruses. In this therapy, viruses are engineered to selectively propagate in tumor cells and reduce toxicity for non-neoplastic tissues. Adenovirus is one of the most frequently employed oncolytic viruses because of its capacity in tumor cell lysis and immune response stimulation. Upregulation of immunostimulatory signals induced by oncolytic adenoviruses (OAds) might significantly remove local immune suppression and amplify antitumor immune responses. Existing genetic engineering technology allows us to design OAds with increasingly better tumor tropism, selectivity, and antitumor efficacy. Several promising strategies to modify the genome of OAds have been applied: capsid modifications, small deletions in the pivotal viral genes, insertion of tumor-specific promoters, and addition of immunostimulatory transgenes. OAds armed with tumor-associated antigen (TAA) transgenes as cancer vaccines provide additional therapeutic strategies to trigger tumor-specific immunity. Furthermore, the combination of OAds and immune checkpoint inhibitors (ICIs) increases clinical benefit as evidence shown in completed and ongoing clinical trials, especially in the combination of OAds with antiprogrammed death 1/programed death ligand 1 (PD-1/PD-L1) therapy. Despite remarkable antitumor potency, oncolytic adenovirus immunotherapy is confronted with tough challenges such as antiviral immune response and obstruction of tumor microenvironment (TME). In this review, we focus on genomic modification strategies of oncolytic adenoviruses and applications of OAds in cancer immunotherapy.

scholarly journals Enhanced Stimulation of Antigen-Specific Immune Responses Against NPM1-Mutated AML

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1292-1292
Author(s):  
Jochen Marlies Greiner ◽  
Vanessa Schneider ◽  
Hubert Schrezenmeier ◽  
Susanne Hofmann ◽  
Marlies Götz
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Checkpoint Inhibitors ◽  
Antibody Therapy ◽  
Immunological Study ◽  
Facs Analysis ◽  
Strong Immune Response ◽  
Cell Responses ◽  
Suitable Target ◽  
Support Research

Abstract Nucleophosmin1 (NPM1) is one of the most frequently mutated genes in AML, is often associated with a favorable prognosis and seems to be a suitable target structure for immunotherapeutic approaches. Other groups and ours described specific immune responses of CD8-positive T cells against immunogenic epitopes derived from the mutational region of NPM1 in AML patients (pts). In this extended immunological study, we investigated immune responses against the mutational epitope of NPM1 but also against other LAA in NPM1 mut compared to NPM1 wt pts. 30 AML pts were analyzed using FACS analysis, tetramer staining and colony forming immunoassays (CFI). 15 NPM1 mut and 15 NPM1 wt pts were investigated in CFI to detect CTL mediated immune responses against leukemic progenitor/stem cells (LPC/LSC). We also added immune checkpoint inhibitors to investigate whether these immune responses could be enhanced. Against the LAA PRAME-P3, WT1 and RHAMM-R3 we detected similar frequencies of T cell responses in CFI in NPM1 mut compared to NPM1 wt pts. Antigen specific immune responses were detected in CFI by comparing growth of patient cells alone with growth by addition of antigen specific CTL and calculating colony reduction. Comparing NPM1 mut/NPM1 wt pts many had an immune response to LAA, more than 50% of the pts in both cohorts exhibited an immune response against all epitopes. In NPM1 wt pts no responses were found against the NPM1 epitope as expected, whereas NPM1 mut patients showed a high frequency of immune responses in 10/15 NPM1 mut AML pts (67%) in CFI a reduction of colonies was detected. With the addition of anti-PD1 antibody to CFI we detected an increase of immune responses. For the LAA responses were similar comparing NPM1 mut/NPM1 wt. Compared to LAA, the epitope NPM1 showed a particularly strong immune response when the antibody anti-PD1 was added. All 15 NPM1 mut pts showed an immune response with anti-PD1, with a median reduction of colonies of 47%. 7 of 15 NPM1 mut pts showed a strong immune response against LPC/LSC in CFI with more than 50% reduction of colonies. The data suggest that especially NPM1 mut patients are suitable candidates for antibody therapy with the PD1 antibody. Combination with another immunotherapy such as an NPM1 specific vaccine would be a possibility. Even though no advantage in therapy with the anti-PD1 antibody has yet been shown in the overall AML collective, this therapy could be an option for patients with NPM1 mutated AML. Disclosures Greiner: Bristol Myers Squibb: Other: Unspecified Relationship. Schneider: AbbVie: Current Employment. Schrezenmeier: Novartis: Honoraria; Apellis: Honoraria; Sanofi: Honoraria; Alexion, AstraZeneca Rare Disease: Honoraria, Other: Travel support, Research Funding; Roche: Honoraria.

An innovative combined immunization platform for personalized cancer immunotherapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14225-e14225
Author(s):  
Jessica Matta ◽  
Célia Matta ◽  
Emilie Thiebault Peter ◽  
David Moulaert ◽  
Robert Drillien ◽  
...  
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Vector Coding ◽  
Melanoma Model ◽  
Dna Vector ◽  
Personalized Cancer

e14225 Background: Activity of immune checkpoint inhibitors relies mainly on the presence of an immune response directed against neoantigens resulting from tumor specific mutations. The induction and/or amplification of such an immune response is expected to increase the activity of these therapies. We describe here a novel immunization platform developed for the purpose of personalized cancer immunotherapy. This platform integrates a DNA vector coding for neoantigens, a live modified vaccinia of strain Ankara (MVA) used as a physiologic adjuvant and anti-CTLA-4 as a locally acting early immune checkpoint blocker. Methods: Immune potency was assessed in C57BL6 mice injected subcutaneously three times five days apart with an ovalbumine (OVA) expressing DNA vector (100 µg), either alone or in combination with increasing doses of MVA (up to 2.5x107 plaque forming units, pfu) and increasing doses of anti-CTLA-4 (up to 100 µg). OVA specific immune responses were measured by ELISpot. Anti-tumor efficacy was then investigated with a similar administration scheme in a therapeutic B16F10 mice melanoma model with a DNA vector coding for the B16F10-M30 tumor neoantigen. Results: At an optimal dose of 2.5x106 pfu, MVA significantly improved OVA specific immune response up to 10 times higher as compared to vector alone. Addition of CTLA-4 blockade further increased the magnitude of response, up to 30 times higher than with vector alone. Both MVA and CTLA-4 demonstrated a bell-shaped dose dependent effect. In tumor-bearing animals, 80% experienced durable tumor-free survival when treated with the combination therapy as compared to less than 20% in untreated animals or animals treated with each component independently. Treatment appeared feasible and well-tolerated. Conclusions: Neoantigen coding DNA vector, MVA and CTLA-4 immune checkpoint blockade, when co-administered in immunocompetent C57BL6 mice, acted synergistically to induce a cellular immune response. The same approach translated into a strong anti-tumoral response in an aggressive melanoma model. This combined immunization platform appears as a potential novel way to enhance clinical benefit from current immune checkpoint inhibitors.

To do or not to do: A concise update of current clinical controversies in immune checkpoint blockade

2018 ◽  
Vol 25 (3) ◽  
pp. 663-673 ◽  
Author(s):  
Clement Chung
Keyword(s):  
Immune Response ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Immune Checkpoint Blockade ◽  
Cellular Interactions ◽  
Programmed Death Ligand 1 ◽  
Multiple Tumor ◽  
First Line Therapy ◽  
Programmed Death ◽  
Starting Point

Although programmed death-ligand 1 is currently the best available biomarker for first-line therapy with pembrolizumab for patients with non-small cell lung cancer and is a required companion test approved by the US Food and Drug Administration, programmed death-ligand 1 testing is an option (as a complementary test) for patients treated with nivolumab, atezolizumab, and durvalumab. Programmed death-ligand 1 expression is continuously variable and dynamic in the tumor microenvironment. Due to the complex molecular and cellular interactions involved in immune response, a single biomarker may not be sufficient to predict response to cancer immunotherapy. Integration of multiple tumor, immune response, and genomic parameters is likely to influence the future interpretation of biomarker-based treatment outcomes. This article, in a case-based format, concisely summarizes most up-to-date evidence in answering some commonly seen clinical controversies of cancer immunotherapy, in terms of (i) the predictive value of programmed death-ligand 1 as a biomarker; (ii) whether the use of steroids with checkpoint inhibitors will decrease efficacy of the latter; (iii) selection of patients for cancer immunotherapy based on immune-based response criteria, and (iv) whether the use of influenza vaccine with checkpoint inhibitors is considered safe. Until more robust, long-term prospective clinical data are available, these discussions may serve as a starting point for pharmacists to gain timely and effective management of these realistic issues.

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