scholarly journals Utilizing cell-based therapeutics to overcome immune evasion in hematologic malignancies

Blood ◽  
2016 ◽  
Vol 127 (26) ◽  
pp. 3350-3359 ◽  
Author(s):  
Chuang Sun ◽  
Gianpietro Dotti ◽  
Barbara Savoldo
Keyword(s):  
Tumor Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Hematologic Malignancies ◽  
Donor Lymphocyte Infusion ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells

Abstract Hematologic malignancies provide a suitable testing environment for cell-based immunotherapies, which were pioneered by the development of allogeneic hematopoietic stem cell transplant. All types of cell-based therapies, from donor lymphocyte infusion to dendritic cell vaccines, and adoptive transfer of tumor-specific cytotoxic T cells and natural killer cells, have been clinically translated for hematologic malignancies. The recent success of chimeric antigen receptor–modified T lymphocytes in B-cell malignancies has stimulated the development of this approach toward other hematologic tumors. Similarly, the remarkable activity of checkpoint inhibitors as single agents has created enthusiasm for potential combinations with other cell-based immune therapies. However, tumor cells continuously develop various strategies to evade their immune-mediated elimination. Meanwhile, the recruitment of immunosuppressive cells and the release of inhibitory factors contribute to the development of a tumor microenvironment that hampers the initiation of effective immune responses or blocks the functions of immune effector cells. Understanding how tumor cells escape from immune attack and favor immunosuppression is essential for the improvement of immune cell–based therapies and the development of rational combination approaches.

Adoptive Immune Cell Therapy for the Control of Fungal Infections in Hematopoietic Stem Cell Transplant Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4358-4358
Author(s):  
Lung-Ji Chang ◽  
Yin Liang ◽  
Lily Lien ◽  
Chun- Rong Tong ◽  
Lu-Jia Dong ◽  
...  
Keyword(s):  
Immune Cells ◽  
Immune Cell ◽  
Fungal Infections ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Effector ◽  
Effector Cells ◽  
Transplant Patients ◽  
Fungal Antigens ◽  
Anti Fungal

Abstract Similar to virus infections, fungal infections are commonly seen in immunosuppressed transplant patients and can be life-threatening. Invasive Aspergillosis and Candidiasis are principal fungal infections among hematopoietic stem cell transplant (HSCT) patients, but Aspergillosis and other molds are the leading cause of deaths by fungal infections in immunocompromised allogeneic HSCT patients. The most effective treatment for fungal infections is preemptive and empirical anti-fungal therapies using agents such as fluconazole and amphotericin B deoxycholate (AmB-D). However, the success rate of antifungal therapy is generally low (in the 30–40% range) and associated with high toxicity. Both diagnosis and treatment for fungal infections are expensive and often ineffective. While improved formulations of AmB-D, second-generation triazoles, and echinocandins may be tolerable, newer generations of anti-fungal agents are very expensive. In animal studies, it has been shown that Aspergillosis can be successfully treated using Aspergillus-specific cytotoxic T cells (CTLs). Therefore, it is conceivable that CTLs specific to fungal antigens are effective in controlling fungal infections in allogeneic HSCT patients. To explore anti-fungal immune cell therapy, we used two different approaches to generate fungus-specific immune cells: Trichoderma and Rhizopus fungal lysates as antigen source to pulse dendritic cells (DCs), and pooled antigenic peptides to pulse DCs. The antigen-primed DCs were then co-cultured with lymphocytes to generate antigen-specific immune effector cells. The ex vivo generated anti-fungal immune cells displayed antigen-specific effector functions as illustrated by intracellular IFN-γ and CD107a staining. Interestingly, the fungus-specific immune effector cells are mostly CD4 T cells for all three species of fungal antigens. In a pilot clinical study, patients were selected when diagnosed with invasive aspergillosis based on galactomannan and beta-glucan assays, radiographs, CT scans, and/or blood cultures, or after an extended unsuccessful anti-fungal treatment with non-tolerable organ toxicity. Early indications suggest that the infusion of anti-fungal immune cells is safe, with therapeutic efficacy based on objective clinical evidence and importantly, is cost-effective. Nevertheless, more effective diagnosis and surveillance tools are needed to document the effectiveness of our anti-fungal immune cell treatment.

scholarly journals Predictive Biomarkers of Immune Checkpoint Inhibitor Response in Breast Cancer: Looking beyond Tumoral PD-L1

Biomedicines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1863
Author(s):  
Nan Chen ◽  
Nicole Higashiyama ◽  
Valentina Hoyos
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Immune Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Large Scale ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Cytotoxic T Cells ◽  
Predictive Biomarkers

Immune checkpoint inhibitors utilize the immune system to kill cancer cells and are now widely applied across numerous malignancies. Pembrolizumab has two breast-specific indications in triple-negative disease. Currently, programmed death ligand-1 (PD-L1) expression on tumor and surrounding immune cells is the only validated predictive biomarker for immune checkpoint inhibitors (ICIs) in breast cancer; however, it can be imprecise. Additional biomarkers are needed to identify the patient population who will derive the most benefit from these therapies. The tumor immune microenvironment contains many biomarker candidates. In tumor cells, tumor mutational burden has emerged as a robust biomarker across malignancies in general, with higher burden cancers demonstrating improved response, but will need further refinement for less mutated cancers. Preliminary studies suggest that mutations in breast cancer gene 2 (BRCA-2) are associated with increased immune infiltration and response to ICI therapy. Other genomic alterations are also being investigated as potential predictive biomarkers. In immune cells, increased quantity of tumor-infiltrating lymphocytes and CD8+ cytotoxic T cells have correlated with response to immunotherapy treatment. The role of other immune cell phenotypes is being investigated. Peripherally, many liquid-based biomarker strategies such as PD-L1 expression on circulating tumor cells and peripheral immune cell quantification are being studied; however, these strategies require further standardization and refinement prior to large-scale testing. Ultimately, multiple biomarkers utilized together may be needed to best identify the appropriate patients for these treatments.

scholarly journals Clonal hematopoiesis and its emerging effects on cellular therapies

Leukemia ◽  
2021 ◽  
Author(s):  
Malte von Bonin ◽  
Helena Klara Jambor ◽  
Raphael Teipel ◽  
Friedrich Stölzel ◽  
Christian Thiede ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Hematologic Malignancies ◽  
T Cell Therapy ◽  
Hematopoietic Stem ◽  
Cell Therapies ◽  
Immune Effector ◽  
Effector Cells ◽  
Clonal Hematopoiesis ◽  
Inflammatory Conditions ◽  
Inflammatory Phenotype

AbstractThe accumulation of somatic mutations in hematopoietic stem cells during aging, leading to clonal expansion, is linked to a higher risk of cardiovascular mortality and hematologic malignancies. Clinically, clonal hematopoiesis is associated with a pro-inflammatory phenotype of hematopoietic cells and their progeny, inflammatory conditions and a poor outcome for patients with hematologic neoplasms and solid tumors. Here, we review the relevance and complications of clonal hematopoiesis for the treatment of hematologic malignancies with cell therapeutic approaches. In autologous and allogeneic hematopoietic stem cell transplantation native hematopoietic and immune effector cells of clonal origin are transferred, which may affect outcome of the procedure. In chimeric antigen receptor modified T-cell therapy, the effectiveness may be altered by preexisting somatic mutations in genetically modified effector cells or by unmodified bystander cells harboring clonal hematopoiesis. Registry studies and carefully designed prospective trials will be required to assess the relative roles of donor- and recipient-derived individual clonal events for autologous and allogeneic cell therapies and to incorporate novel insights into therapeutic strategies.

scholarly journals Autoimmune Complications in Hematologic Neoplasms

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1532
Author(s):  
Wilma Barcellini ◽  
Juri Alessandro Giannotta ◽  
Bruno Fattizzo
Keyword(s):  
Lupus Erythematosus ◽  
Checkpoint Inhibitors ◽  
Myeloproliferative Neoplasms ◽  
Pure Red Cell Aplasia ◽  
Lymphocytic Leukemia ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Hematopoietic Stem ◽  
Non Hodgkin Lymphoma ◽  
Diagnostic Difficulties

Autoimmune cytopenias (AICy) and autoimmune diseases (AID) can complicate both lymphoid and myeloid neoplasms, and often represent a diagnostic and therapeutic challenge. While autoimmune hemolytic anemia (AIHA) and immune thrombocytopenia (ITP) are well known, other rarer AICy (autoimmune neutropenia, aplastic anemia, and pure red cell aplasia) and AID (systemic lupus erythematosus, rheumatoid arthritis, vasculitis, thyroiditis, and others) are poorly recognized. This review analyses the available literature of the last 30 years regarding the occurrence of AICy/AID in different onco-hematologic conditions. The latter include chronic lymphocytic leukemia (CLL), lymphomas, multiple myeloma, myelodysplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML), myeloproliferative neoplasms, and acute leukemias. On the whole, AICy are observed in up to 10% of CLL and with higher frequencies in certain subtypes of non-Hodgkin lymphoma, whilst they occur in less than 1% of low-risk MDS and CMML. AID are described in up to 30% of myeloid and lymphoid patients, including immune-mediated hemostatic disorders (acquired hemophilia, thrombotic thrombocytopenic purpura, and anti-phospholipid syndrome) that may be severe and fatal. Additionally, AICy/AID are found in about 10% of patients receiving hematopoietic stem cell transplant or treatment with new checkpoint inhibitors. Besides the diagnostic difficulties, these AICy/AID may complicate the clinical management of already immunocompromised patients.

scholarly journals Immune Therapies for Hematologic Malignancies

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 295
Author(s):  
Matthew J. Olnes
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem Cell Transplant ◽  
Stem Cell Transplant ◽  
Hematologic Malignancies ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Immune Therapies

The era of immunotherapy for hematologic malignancies began with the first allogeneic hematopoietic stem cell transplant (HSCT) study published by E [...]

scholarly journals 205. Rectal Stool Surveillance Cultures to Guide Empiric Antibiotic Therapy in Patients with Hematologic Malignancies with or without Hematopoietic Stem Cell Transplantation

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S106-S106
Author(s):  
Afrah S Sait ◽  
Shalom S Patole ◽  
Kathryn Dzintars ◽  
Sara E Cosgrove ◽  
Seema Mehta Steinke
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Broad Spectrum ◽  
Hematologic Malignancies ◽  
Adult Patients ◽  
Empiric Antibiotic Therapy ◽  
Lower Probability ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Surveillance Cultures

Abstract Background Patients with hematologic malignancies (HM) or hematopoietic stem cell transplant (HSCT) commonly receive broad-spectrum antimicrobials, often leading to the development of multidrug resistant organisms (MDRO). At our institution, rectal stool surveillance cultures (SSC) are done weekly on admitted adult patients with HMs or HSCT. The objective of this study is to determine the role of SSCs in predicting the development of a sterile site infection (StSI) with the same MDRO as identified in the SSC. Methods We retrospectively evaluated StSIs (blood, CSF, sputum/respiratory, pleural fluid, and urine) and SSC data from 242 adult patients admitted to the adult oncology ward at a large academic tertiary care center from 6/1/2017 to 2/28/2019. Demographics, SSC data, and StSIs in a 3-month period following the last SSC for each patient were collected from electronic medical records. SSCs were cultured on HardyCHROM ESBL™ media. MDRO similarity between SSC and StSI was determined by comparing susceptibility profiles. JMPÒ Pro 14.3.0 and RStudio were used for statistical analyses. Results Two hundred forty-two patients yielded 732 SSCs. We eliminated SSCs with incomplete (< 3 months of follow up) data. Thus, 579 SSCs were included in the analyses. 64% of patients were male. Leukemias (55.4%), lymphomas (21.9%), and multiple myeloma (10.3%) were the most common HMs. HSCT recipients comprised 50.4%. SSCs were positive for a MDRO in 251 cases (vancomycin-resistant enterococci, 52.2%; extended-spectrum beta-lactamase (ESBL) producing organisms, 22.2%; and carbapenamase producing organisms, 4.4%). There were 54 StSIs documented where the MDRO was the same as the SSC MDRO. The NPV of the SSC was 95.1% (95%CI 0.93,0.97). The positive likelihood ratio of the SSC was 2.5 (95%CI 2.07,3.02). Conclusion Our results suggest that a negative SSC is associated with a lower probability of identifying a StSI with an MDRO. Clinically, this can be useful in providing the opportunity to judiciously guide antimicrobial therapy, thereby avoiding the unnecessary usage of broad-spectrum antimicrobials when no MDRO is identified in the SSC. Disclosures All Authors: No reported disclosures

scholarly journals Targeting HIF-1 alpha transcriptional activity drives cytotoxic immune effector cells into melanoma and improves combination immunotherapy

Oncogene ◽  
2021 ◽  
Author(s):  
Audrey Lequeux ◽  
Muhammad Zaeem Noman ◽  
Malina Xiao ◽  
Kris Van Moer ◽  
Meriem Hasmim ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Cancer Immunotherapy ◽  
Transcriptional Activity ◽  
Immune Cell ◽  
Tumor Resistance ◽  
Combination Strategy ◽  
Immune Effector ◽  
Effector Cells ◽  
Melanoma Patients ◽  
The Impact

AbstractHypoxia is a key factor responsible for the failure of therapeutic response in most solid tumors and promotes the acquisition of tumor resistance to various antitumor immune effectors. Reshaping the hypoxic immune suppressive tumor microenvironment to improve cancer immunotherapy is still a relevant challenge. We investigated the impact of inhibiting HIF-1α transcriptional activity on cytotoxic immune cell infiltration into B16-F10 melanoma. We showed that tumors expressing a deleted form of HIF-1α displayed increased levels of NK and CD8+ effector T cells in the tumor microenvironment, which was associated with high levels of CCL2 and CCL5 chemokines. We showed that combining acriflavine, reported as a pharmacological agent preventing HIF-1α/HIF-1β dimerization, dramatically improved the benefit of cancer immunotherapy based on TRP-2 peptide vaccination and anti-PD-1 blocking antibody. In melanoma patients, we revealed that tumors exhibiting high CCL5 are less hypoxic, and displayed high NK, CD3+, CD4+ and CD8+ T cell markers than those having low CCL5. In addition, melanoma patients with high CCL5 in their tumors survive better than those having low CCL5. This study provides the pre-clinical proof of concept for a novel triple combination strategy including blocking HIF-1α transcription activity along vaccination and PD-1 blocking immunotherapy.

scholarly journals Participation of the H-2 antigens of tumor cells in their lysis by syngeneic T cells.

1976 ◽  
Vol 143 (3) ◽  
pp. 601-614 ◽  
Author(s):  
J W Schrader ◽  
G M Edelman
Keyword(s):  
T Cells ◽  
Tumor Cell ◽  
Tumor Cells ◽  
Target Cell ◽  
Cytotoxic T Cells ◽  
Hybrid Origin ◽  
Target Cells ◽  
Cytotoxic Lymphocytes ◽  
Effector Cells

Cytotoxic T lymphocytes were generated in vitro against H-2 compatible or syngeneic tumor cells. In vitro cytotoxic activity was inhibited by specific anti-H2 sera, suggesting that H-2 antigens are involved in cell lysis. Two observations directly demonstrated the participation of the H-2 antigens on the tumor cells in their lysis by H-2-compatible T cells. First, coating of the H-2 antigens on the target tumor cell reduced the number of cells lysed on subsequent exposure to cytotoxic T cells. Second, when cytotoxic T cells were activated against an H-2 compatible tumor and assayed against an H-2-incompatible tumor, anti-H-2 serum that could bind to the target cell, but not to the cytotoxic lymphocyte, inhibited lysis. H-2 antigens were also shown to be present on the cytotoxic lymphocytes. Specific antisera reacting with these H-2 antigens, but not those of the target cell, failed to inhibit lysis when small numbers of effector cells were assayed against H-2-incompatible target cells or when effector cells of F1-hybrid origin and bearing two H-2 haplotypes were assayed against a tumor cell of one of the parental strains. These findings suggest that it is the H-2 antigens on the tumor cell and not those on the cytotoxic lymphocytes that are important in cell-mediated lysis of H-2-compatible tumor cells.

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