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1.
J Hematol Oncol ; 15(1): 81, 2022 06 16.
Article in English | MEDLINE | ID: covidwho-1962866

ABSTRACT

Recipients after hematopoietic stem cell transplantation (HSCT) or chimeric antigen receptor T-cell (CAR-T) therapy are at increased risk for unfavorable outcomes after SARS-CoV-2 infection. The efficacy of COVID-19 vaccines remains undetermined in this vulnerable population, we therefore conducted a pooled analysis to evaluate the immune response after vaccination. A total of 46 studies were finally included, comprising 4757 HSCT and 174 CAR-T recipients. Our results indicated that HSCT and CAR-T recipients had an attenuated immune response to SARS-CoV-2 vaccination compared with healthy individuals, while time interval between transplant and vaccination, immunosuppressive therapy (IST) and lymphocyte counts at vaccination significantly affected the humoral response in HSCT recipients. In addition, seroconversion was significantly higher in patients with BCMA-based CAR-T than those with CD19-based CAR-T. Thus, an adapted vaccination strategy for HSCT and CAR-T recipients may be required, and further research on the effect of a booster dose of COVID-19 vaccine and the role of cellular response after vaccination is warranted.


Subject(s)
COVID-19 , Hematopoietic Stem Cell Transplantation , Receptors, Chimeric Antigen , Antibodies, Viral , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Hematopoietic Stem Cell Transplantation/methods , Humans , Immunity , Immunotherapy, Adoptive/methods , SARS-CoV-2 , Vaccination
2.
J Transl Med ; 20(1): 338, 2022 07 28.
Article in English | MEDLINE | ID: covidwho-1962854

ABSTRACT

BACKGROUND: Cytokine release syndrome (CRS) is a strong immune system response that can occur as a result of the reaction of a cellular immunotherapy with malignant cells. While the frequency and management of CRS in CAR T-cell therapy has been well documented, there is emerging interest in pre-emptive treatment to reduce CRS severity and improve overall outcomes. Accordingly, identification of genomic determinants that contribute to cytokine release may lead to the development of targeted therapies to prevent or abrogate the severity of CRS. METHODS: Forty three clinical CD22 CAR T-cell products were collected for RNA extraction. 100 ng of mRNA was used for Nanostring assay analysis which is based on the nCounter platform. Several public datasets were used for validation purposes. RESULTS: We found the expression of the PFKFB4 gene and glycolytic pathway activity were upregulated in CD22 CAR T-cells given to patients who developed CRS compared to those who did not experience CRS. Moreover, these results were further validated in cohorts with COVID-19, influenza infections and autoimmune diseases, and in tumor tissues. The findings were similar, except that glycolytic pathway activity was not increased in patients with influenza infections and systemic lupus erythematosus (SLE). CONCLUSION: Our data strongly suggests that PFKFB4 acts as a driving factor in mediating cytokine release in vivo by regulating glycolytic activity. Our results suggest that it would beneficial to develop drugs targeting PFKFB4 and the glycolytic pathway for the treatment of CRS.


Subject(s)
COVID-19 , Influenza, Human , COVID-19/therapy , Cytokine Release Syndrome , Cytokines/metabolism , Genomics , Humans , Immunotherapy , Immunotherapy, Adoptive/methods , Phosphofructokinase-2 , Receptors, Chimeric Antigen
3.
Int J Mol Sci ; 23(13)2022 Jun 24.
Article in English | MEDLINE | ID: covidwho-1934121

ABSTRACT

Natural killer cells are innate lymphocytes with the ability to lyse tumour cells depending on the balance of their activating and inhibiting receptors. Growing numbers of clinical trials show promising results of NK cell-based immunotherapies. Unlike T cells, NK cells can lyse tumour cells independent of antigen presentation, based simply on their activation and inhibition receptors. Various strategies to improve NK cell-based therapies are being developed, all with one goal: to shift the balance to activation. In this review, we discuss the current understanding of ways NK cells can lyse tumour cells and all the inhibitory signals stopping their cytotoxic potential.


Subject(s)
Immunotherapy, Adoptive , Neoplasms , Humans , Immunotherapy , Immunotherapy, Adoptive/methods , Killer Cells, Natural , Neoplasms/therapy , T-Lymphocytes
8.
Front Immunol ; 11: 624411, 2020.
Article in English | MEDLINE | ID: covidwho-1389173

ABSTRACT

SARS-CoV-2 is wreaking havoc around the world. To get the world back on track, hundreds of vaccines are under development. A deeper understanding of how the immune system responds to SARS-CoV-2 re-infection will certainly help. Studies have highlighted various aspects of T cell response in resolving acute infection and preventing re-infections. Lung resident memory T (TRM) cells are sentinels in the secondary immune response. They are mostly differentiated from effector T cells, construct specific niches and stay permanently in lung tissues. If the infection recurs, locally activated lung TRM cells can elicit rapid immune response against invading pathogens. In addition, they can significantly limit tumor growth or lead to pathologic immune responses. Vaccines targeting TRM cells are under development, with the hope to induce stable and highly reactive lung TRM cells through mucosal administration or "prime-and-pull" strategy. In this review, we will summarize recent advances in lung TRM cell generation and maintenance, explore their roles in different diseases and discuss how these cells may guide the development of future vaccines targeting infectious disease, cancer, and pathologic immune response.


Subject(s)
COVID-19/immunology , Immunotherapy, Adoptive/methods , Lung/immunology , Neoplasms/immunology , SARS-CoV-2/physiology , T-Lymphocytes/immunology , Vaccines/immunology , Animals , Humans , Immunologic Memory , Lymphocyte Activation , T-Lymphocytes/transplantation
10.
Front Immunol ; 12: 655122, 2021.
Article in English | MEDLINE | ID: covidwho-1365539

ABSTRACT

FOXP3+ regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor α-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies.


Subject(s)
Gene Editing/methods , Interleukin-2 Receptor alpha Subunit/genetics , Receptors, Interleukin-6/genetics , T-Lymphocytes, Regulatory/metabolism , Blood Buffy Coat/cytology , CRISPR-Cas Systems/genetics , Forkhead Transcription Factors/metabolism , Gene Knockdown Techniques , HEK293 Cells , Healthy Volunteers , Humans , Immunotherapy, Adoptive/methods , Primary Cell Culture , RNA, Guide/genetics , Time Factors
11.
Cells ; 10(6)2021 06 19.
Article in English | MEDLINE | ID: covidwho-1273394

ABSTRACT

COVID-19 is an acute infectious disease of the respiratory system caused by infection with the SARS-CoV-2 virus (Severe Acute Respiratory Syndrome Coronavirus 2). Transmission of SARS-CoV-2 infections occurs through droplets and contaminated objects. A rapid and well-coordinated immune system response is the first line of defense in a viral infection. However, a disturbed and over-activated immune response may be counterproductive, causing damage to the body. Severely ill patients hospitalised with COVID-19 exhibit increased levels of many cytokines, including Interleukin (IL)-1ß, IL-2, IL-6, IL-7, IL-8, IL-10, IL-17, granulocyte colony stimulating factor (G-CSF), monocyte chemoattractant protein 1 (MCP-1) and tumor necrosis factor (TNF). Increasing evidence suggests that Th17 cells play an important role in the pathogenesis of COVID-19, not only by activating cytokine cascade but also by inducing Th2 responses, inhibiting Th1 differentiation and suppressing Treg cells. This review focuses on a Th17 pathway in the course of the immune response in COVID-19, and explores plausible targets for therapeutic intervention.


Subject(s)
COVID-19/immunology , Immunity, Cellular/physiology , Th17 Cells/physiology , COVID-19/pathology , COVID-19/therapy , Cytokines/metabolism , Humans , Immunotherapy, Adoptive/methods , SARS-CoV-2/immunology , Th17 Cells/metabolism
12.
JCO Clin Cancer Inform ; 5: 668-678, 2021 06.
Article in English | MEDLINE | ID: covidwho-1264197

ABSTRACT

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell-associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments-based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T-related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.


Subject(s)
Cytokine Release Syndrome/etiology , Immunotherapy, Adoptive/adverse effects , Telemedicine/methods , COVID-19 , Cell- and Tissue-Based Therapy/adverse effects , Humans , Immunotherapy, Adoptive/methods , Machine Learning , Neurotoxicity Syndromes/etiology , Precision Medicine , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen
13.
Ann Clin Transl Neurol ; 8(4): 968-979, 2021 04.
Article in English | MEDLINE | ID: covidwho-1155205

ABSTRACT

OBJECTIVE: Many neurological manifestations are associated with COVID-19, including a distinct form of encephalopathy related to cytokine storm, the acute systemic inflammatory syndrome present in a subgroup of COVID-19 patients. Cytokine storm is also associated with immune effector cell-associated neurotoxicity syndrome (ICANS), a complication of chimeric antigen receptor T-cell (CAR-T) therapy, a highly effective treatment for refractory hematological malignancies. We investigated whether COVID-19-related encephalopathy, ICANS, and other encephalopathies associated with cytokine storm, share clinical and investigative findings. METHODS: Narrative literature review. RESULTS: Comparisons between COVID-19-related encephalopathy and ICANS revealed several overlapping features. Clinically, these included dysexecutive syndrome, language disturbances, akinetic mutism and delirium. EEG showed a prevalence of frontal abnormalities. Brain MRI was often unrevealing. CSF elevated cytokine levels have been reported. A direct correlation between cytokine storm intensity and severity of neurological manifestations has been shown for both conditions. Clinical recovery occurred spontaneously or following immunotherapies in most of the patients. Similar clinical and investigative features were also reported in other encephalopathies associated with cytokine storm, such as hemophagocytic lymphohistiocytosis, sepsis, and febrile infection-associated encephalopathies. INTERPRETATION: COVID-19-related encephalopathy and ICANS are characterized by a predominant electro-clinical frontal lobe dysfunction and share several features with other encephalopathies associated with cytokine storm, which may represent the common denominator of a clinical spectrum of neurological disorders. Therefore, we propose a unifying definition of cytokine storm-associated encephalopathy (CySE), and its diagnostic criteria.


Subject(s)
Brain Diseases/physiopathology , Brain/physiopathology , COVID-19/physiopathology , Cytokine Release Syndrome/physiopathology , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen , Brain Diseases/epidemiology , Brain Diseases/therapy , COVID-19/epidemiology , COVID-19/therapy , Cytokine Release Syndrome/epidemiology , Cytokine Release Syndrome/therapy , Humans , Immunotherapy, Adoptive/trends
14.
Int J Mol Sci ; 22(5)2021 Feb 28.
Article in English | MEDLINE | ID: covidwho-1120888

ABSTRACT

Immunotherapy is a highly emerging form of breast cancer therapy that enables clinicians to target cancers with specific receptor expression profiles. Two popular immunotherapeutic approaches involve chimeric antigen receptor-T cells (CAR-T) and bispecific antibodies (BsAb). Briefly mentioned in this review as well is the mRNA vaccine technology recently popularized by the COVID-19 vaccine. These forms of immunotherapy can highly select for the tumor target of interest to generate specific tumor lysis. Along with improvements in CAR-T, bispecific antibody engineering, and therapeutic administration, much research has been done on novel molecular targets that can especially be useful for triple-negative breast cancer (TNBC) immunotherapy. Combining emerging immunotherapeutics with tumor marker discovery sets the stage for highly targeted immunotherapy to be the future of cancer treatments. This review highlights the principles of CAR-T and BsAb therapy, improvements in CAR and BsAb engineering, and recently identified human breast cancer markers in the context of in vitro or in vivo CAR-T or BsAb treatment.


Subject(s)
Breast Neoplasms/therapy , Immunotherapy/methods , Animals , Antibodies, Bispecific/immunology , Antibodies, Bispecific/therapeutic use , Biomarkers, Tumor , Breast Neoplasms/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19 Vaccines/immunology , Cancer Vaccines/administration & dosage , Cancer Vaccines/immunology , Female , Humans , Immunotherapy, Adoptive/methods , Molecular Targeted Therapy , Receptors, Chimeric Antigen/immunology , SARS-CoV-2/immunology , Triple Negative Breast Neoplasms/immunology , Triple Negative Breast Neoplasms/therapy , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunology
15.
J Med Case Rep ; 15(1): 90, 2021 Feb 19.
Article in English | MEDLINE | ID: covidwho-1090621

ABSTRACT

BACKGROUND: Very little is known about the risk that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection poses to cancer patients, many of whom are immune compromised causing them to be more susceptible to a host of infections. As a precautionary measure, many clinical studies halted enrollment during the initial surge of the global Novel Coronavirus Disease (COVID-19) pandemic. In this case report, we detail the successful treatment of a relapsed and refractory multiple myeloma (MM) patient treated with an anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cell therapy immediately following clinical recovery from COVID-19. CASE PRESENTATION: The 57 year old Caucasian male patient had a 4-year history of MM and was considered penta-refractory upon presentation for CAR T cell therapy. He had a history of immunosuppression and received one dose of lymphodepleting chemotherapy (LDC) the day prior to COVID-19 diagnosis; this patient was able to mount a substantial immune response against the SARS-CoV-2 virus, and antiviral antibodies remain detectable 2 months after receiving anti-BCMA CAR T cell therapy. The recent SARS-CoV-2 infection in this patient did not exacerbate CAR T-associated cytokine release syndrome (CRS) and conversely the CAR T cell therapy did not result in COVID-19-related complications. One month after CAR T cell infusion, the patient was assessed to have an unconfirmed partial response per International Myeloma Working Group (IMWG) criteria. CONCLUSION: Our case adds important context around treatment choice for MM patients in the era of COVID-19 and whether CAR T therapy can be administered to patients who have recovered from COVID-19. As the COVID-19 global pandemic continues, the decision of whether to proceed with CAR T cell therapy will require extensive discussion weighing the potential risks and benefits of therapy. This case suggests that it is possible to successfully complete anti-BCMA CAR T cell therapy after recovery from COVID-19. CRB-402 study registered 6 September 2017 at clinicaltrials.gov (NCT03274219).


Subject(s)
B-Cell Maturation Antigen/immunology , COVID-19/physiopathology , Immunotherapy, Adoptive/methods , Multiple Myeloma/therapy , Receptors, Chimeric Antigen/immunology , Antibodies, Viral/immunology , COVID-19/complications , COVID-19/diagnosis , COVID-19/immunology , COVID-19 Nucleic Acid Testing , COVID-19 Serological Testing , Cough , Cyclophosphamide/therapeutic use , Disease Progression , Fever , Hospitalization , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Multiple Myeloma/complications , SARS-CoV-2 , Vidarabine/analogs & derivatives , Vidarabine/therapeutic use
17.
Front Immunol ; 11: 573179, 2020.
Article in English | MEDLINE | ID: covidwho-909162

ABSTRACT

The COVID-19 pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has generated a significant repercussion on the administration of adoptive cell therapies, including chimeric antigen receptor (CAR) T-cells. The closing of borders, the reduction of people transit and the confinement of the population has affected the supply chains of these life-saving medical products. The aim of this mini-review is to focus on how the COVID-19 pandemic has affected CAR T-cell therapy and taking into consideration the differences between the large-scale centralized productions for the pharmaceutical industry versus product manufacturing in the academic/hospital environment. We also review different aspects of CAR T-cell therapy and our managerial experience of patient selection, resource prioritization and some practical aspects to consider for safe administration. Although hospitals have been forced to change their usual workflows to cope with the saturation of health services by hospitalized patients, we recommend centers to continue offering this potentially curative treatment for patients with relapsed/refractory hematologic malignancies. Consequently, we propose appropriate selection criteria, early intervention to attenuate neurotoxicity or cytokine release syndrome with tocilizumab and prophylactic/preventive strategies to prevent infection. These considerations may apply to other emerging adoptive cell treatments and the corresponding manufacturing processes.


Subject(s)
COVID-19/epidemiology , COVID-19/prevention & control , Immunotherapy, Adoptive/methods , Point-of-Care Systems , SARS-CoV-2 , Antibodies, Monoclonal, Humanized/therapeutic use , Antigens, CD19/immunology , COVID-19/virology , Cytokine Release Syndrome/drug therapy , Health Services Accessibility , Health Workforce , Hematologic Neoplasms/therapy , Humans , Patient Selection , Triage
18.
Blood ; 136(25): 2905-2917, 2020 12 17.
Article in English | MEDLINE | ID: covidwho-890058

ABSTRACT

T-cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been described in recovered patients, and may be important for immunity following infection and vaccination as well as for the development of an adoptive immunotherapy for the treatment of immunocompromised individuals. In this report, we demonstrate that SARS-CoV-2-specific T cells can be expanded from convalescent donors and recognize immunodominant viral epitopes in conserved regions of membrane, spike, and nucleocapsid. Following in vitro expansion using a good manufacturing practice-compliant methodology (designed to allow the rapid translation of this novel SARS-CoV-2 T-cell therapy to the clinic), membrane, spike, and nucleocapsid peptides elicited interferon-γ production, in 27 (59%), 12 (26%), and 10 (22%) convalescent donors (respectively), as well as in 2 of 15 unexposed controls. We identified multiple polyfunctional CD4-restricted T-cell epitopes within a highly conserved region of membrane protein, which induced polyfunctional T-cell responses, which may be critical for the development of effective vaccine and T-cell therapies. Hence, our study shows that SARS-CoV-2 directed T-cell immunotherapy targeting structural proteins, most importantly membrane protein, should be feasible for the prevention or early treatment of SARS-CoV-2 infection in immunocompromised patients with blood disorders or after bone marrow transplantation to achieve antiviral control while mitigating uncontrolled inflammation.


Subject(s)
CD4-Positive T-Lymphocytes/immunology , COVID-19/immunology , Cell Culture Techniques/methods , Immunotherapy, Adoptive/methods , SARS-CoV-2/immunology , Adult , Aged , COVID-19/drug therapy , Epitopes, T-Lymphocyte/immunology , Female , Humans , Immunodominant Epitopes/immunology , Male , Membrane Proteins/immunology , Middle Aged , Viral Proteins/immunology , Young Adult
20.
Curr Res Transl Med ; 68(3): 111-118, 2020 08.
Article in English | MEDLINE | ID: covidwho-622221

ABSTRACT

The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly across the world. Currently, the COVID-19 pandemic is affecting the continuity of essential routine healthcare services and procedures, including chimeric antigen receptor T-cell (CAR-T) therapy, a life-saving option for patients with relapsed/refractory (R/R) hematologic malignancies. Due to the rapid disease progression of hematological malignancies, there is an urgent need to manufacture and utilize CAR T-cells. However, CAR-T treatment has become extraordinarily challenging during this COVID-19 pandemic. Thus, many medical and technical factors must now be taken into consideration before, during, and after CAR-T therapy. The purpose of this review is to provide brief suggestions for rational decision-making strategies in evaluating and selecting CAR T-cell treatment and appropriate CAR T-cell products, and protective strategies for medical staff and patients to prevent infection in the midst of the current COVID-19 pandemic.


Subject(s)
Coronavirus Infections/prevention & control , Delivery of Health Care/organization & administration , Hematologic Neoplasms/therapy , Immunotherapy, Adoptive , Infection Control/organization & administration , Pandemics/prevention & control , Pneumonia, Viral/prevention & control , Receptors, Antigen, T-Cell/immunology , Betacoronavirus/physiology , COVID-19 , Coronavirus Infections/epidemiology , Delivery of Health Care/methods , Delivery of Health Care/standards , Delivery of Health Care/trends , Hematologic Neoplasms/epidemiology , Humans , Immunotherapy, Adoptive/methods , Immunotherapy, Adoptive/trends , Infection Control/methods , Infection Control/standards , Infection Control/trends , Pneumonia, Viral/epidemiology , Preventive Health Services/methods , Preventive Health Services/organization & administration , Preventive Health Services/standards , Preventive Health Services/trends , SARS-CoV-2
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