Cardiotoxicity associated with immune checkpoint inhibitors and CAR T-cell therapy

2021 ◽  
Author(s):  
Demis N. Lipe ◽  
Eva Rajha ◽  
Adriana H. Wechsler ◽  
Susan Gaeta ◽  
Nicolas L. Palaskas ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Immunotherapy: enhancing the efficacy of this promising therapeutic in multiple cancers

2019 ◽  
Vol 133 (2) ◽  
pp. 181-193 ◽  
Author(s):  
Jitwadee Inthagard ◽  
Joanne Edwards ◽  
Antonia K. Roseweir
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Treatment Outcomes ◽  
Checkpoint Inhibitors ◽  
Tumour Response ◽  
T Cell Therapy ◽  
Multiple Cancers ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Cancer treatments often reach a refractory period leading to treatment failure and patients developing disease recurrence. This can be due to tumour cells escaping the immune response and creating an immunosuppressive microenvironment enhancing cancer progression. Immunotherapy has become a promising tool for cancer treatment as it restores the anti-tumour response of the patient’s immune system. Immune checkpoint inhibitors are the most widely studied immunotherapies worldwide and are now approved for multiple cancers. However, chimeric antigen receptor (CAR)-T cell therapy has also shown promise by targeting T lymphocytes that are genetically modified ex vivo to express CARs and this is now approved to treat some haematological cancers. Although immunotherapy has shown successful treatment outcomes in multiple cancers, some patients do not respond to this treatment. Therefore, approaches to enhance the efficacy of immunotherapies are likely to be the key to improve their effectiveness. Therefore, combination therapies of checkpoint inhibitors +/− chemotherapy are at the forefront of current research. Furthermore, biomarkers that predict treatment response are now beginning to emerge. Additionally, utilising nanoparticles as a newly targeted drug delivery system to enhance CAR-T cell therapy may enhance the efficacy of the cells when re-infused within the patient. Even if efficacy is enhanced, severe immune-related adverse events (irAEs) occur that are life-threatening and could lead to therapy being stopped. Therefore, predictive biomarkers for toxicity are also needed to improve both the patient’s quality of life and treatment outcomes. This review will look at the current immunotherapies in clinical trials and discuss how to enhance their efficacy.

scholarly journals New Frontiers about the Role of Human Microbiota in Immunotherapy: The Immune Checkpoint Inhibitors and CAR T-Cell Therapy Era

2020 ◽  
Vol 21 (23) ◽  
pp. 8902
Author(s):  
Vanessa Innao ◽  
Andrea Gaetano Allegra ◽  
Caterina Musolino ◽  
Alessandro Allegra
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Intestinal Flora ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Programmed Cell Death 1 ◽  
Car T

Microbiota is considered an independent organ with the capability to modulate tumor growth and response to therapies. In the chemo-free era, the use of new immunotherapies, more selective and effective and less toxic, led to the extension of overall survival of patients, subject to their ability to not stop treatment. This has focused scientists’ attention to optimize responses by understanding and changing microbiota composition. While we have obtained abundant data from studies in oncologic and hematologic patients receiving conventional chemotherapy, we have less data about alterations in intestinal flora in those undergoing immunotherapy, especially based on Chimeric Antigen Receptor (CAR) T-cells. Actually, we know that the efficacy of Programmed Cell Death 1 (PD-1), PD-1 ligand, and Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is improved by probiotics rich in Bifidobacterium spp., while compounds of Bacteroidales and Burkholderiales protect from the development of the anti-CTLA-4-induced colitis in mouse models. CAR T-cell therapy seems to not be interfering with microbiota; however, the numerous previous therapies may have caused permanent damage, thus obscuring the data we might have obtained. Therefore, this review opens a new chapter to transfer known acquisitions to a typology of patients destined to grow.

Disparities in the use of checkpoint inhibitors and CAR T-cell therapy: A systematic review.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18541-e18541
Author(s):  
Devika R. Jutagir ◽  
Adriana Espinosa ◽  
Melissa Lopez ◽  
Burha Rasool ◽  
Taisha Gomez ◽  
...  
Keyword(s):  
Systematic Review ◽  
T Cell ◽  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
The United States ◽  
Treatment Facility ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

e18541 Background: With increasing numbers of newly approved cancer immunotherapy regimens, research is needed to understand whether these costly treatments are equally used by all patients who could benefit from them. The aim of this systematic review was to identify variables linked to whether patients diagnosed with cancer were treated with checkpoint inhibitors and chimeric antigen receptor (CAR) T-cell therapy. Methods: Using the PICO (Patient, Intervention, Comparison, Outcome) framework, we conducted a systematic review searching Medline (New PubMed), Embase.com, and the Cochrane Library (Wiley) for papers published in English between January 1, 1997 and July 27, 2020. Inclusion criteria were: 1) primary, peer-reviewed research article; and 2) article reported variables associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Seven coders independently reviewed titles, abstracts, full texts, and extracted data. The systematic review adhered to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Results: In total, 5958 titles and abstracts and 134 full texts were screened. Sixteen studies were included in final analyses. All were conducted in the United States using data from national databases (N = 15) or electronic medical records (N = 1). Eleven were cross-sectional, and 5 were cohort studies. Studies looked at melanoma (N = 10), non-small cell lung cancer (N = 3), renal cell carcinoma (N = 2), colorectal cancer (N = 1), prostate cancer (N = 1), and hepatobiliary cancer (N = 1). Studies looked at nivolumab (N = 1), pembrolizumab (N = 1), ipilimumab (N = 1), and sipuleucel-T, (N = 1), and 12 studies did not specify medication names. Treatment facility characteristics (N = 9), geographic location within the United States (N = 1), locale classification (N = 2), distance to treatment facility (N = 2), insurance type (N = 9), age (N = 7), race (N = 5), sex (N = 1), income (N = 4), neighborhood educational attainment (N = 2), comorbidities (N = 6), disease stage (N = 1), metastases (N = 3), clinical trial participation (N = 1), recency of diagnosis (N = 2), other treatments received (N = 3), and lesion characteristics (N = 1) were reported to be associated with whether patients were treated with checkpoint inhibitors or CAR T-cell therapy. Other studies found that insurance type (N = 1), race (N = 3), sex (N = 1), other treatments received (N = 1), and lesion characteristics (N = 1) were not associated with receiving checkpoint inhibitors or CAR T-cell therapy. Conclusions: Findings provide evidence of disparate access to checkpoint inhibitors and CAR T-cell therapy. More studies are necessary to thoroughly understand how the factors highlighted in our findings intersect to create and maintain disparities in cancer treatment. This level of information is necessary to create interventions that promote equitable access to novel cancer immunotherapies.

scholarly journals Immune checkpoint blockade and CAR-T cell therapy in hematologic malignancies

2019 ◽  
Vol 12 (1) ◽  
Author(s):  
Hao Wang ◽  
Gurbakhash Kaur ◽  
Alexander I. Sankin ◽  
Fuxiang Chen ◽  
Fangxia Guan ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Hematologic Malignancies ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

scholarly journals Immunotherapy and Its Development for Gynecological (Ovarian, Endometrial and Cervical) Tumors: From Immune Checkpoint Inhibitors to Chimeric Antigen Receptor (CAR)-T Cell Therapy

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 840
Author(s):  
Giuseppe Schepisi ◽  
Chiara Casadei ◽  
Ilaria Toma ◽  
Giulia Poti ◽  
Maria Laura Iaia ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
T Cell Therapy ◽  
Gynecological Tumors ◽  
Car T Cell Therapy ◽  
Car T ◽  
Cancer Types

Gynecological tumors are malignancies with both high morbidity and mortality. To date, only a few chemotherapeutic agents have shown efficacy against these cancer types (only ovarian cancer responds to several agents, especially platinum-based combinations). Within this context, the discovery of immune checkpoint inhibitors has led to numerous clinical studies being carried out that have also demonstrated their activity in these cancer types. More recently, following the development of chimeric antigen receptor (CAR)-T cell therapy in hematological malignancies, this strategy was also tested in solid tumors, including gynecological cancers. In this article, we focus on the molecular basis of gynecological tumors that makes them potential candidates for immunotherapy. We also provide an overview of the main immunotherapy studies divided by tumor type and report on CAR technology and the studies currently underway in the area of gynecological malignancies.

scholarly journals Chimeric Antigen Receptor T Cells Engineered to Secrete CD40 Agonist Antibodies Enhance Antitumor Efficacy

2020 ◽  
Author(s):  
Yajun Zhang ◽  
Pei Wang ◽  
tengjiao wang ◽  
Yuan Fang ◽  
Yongmei Ding ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Checkpoint Inhibitors ◽  
Antitumor Efficacy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract BackgroundAlthough chimeric antigen receptor (CAR) T-cell therapy has made remarkable achievements against hematological malignancies, the efficacy of it against solid tumors has been limited. By being combined with immune checkpoint inhibitors, such as PD-1, PD-L1, or CTLA-4 antibodies, this therapy has been shown to be a promising strategy to enhance the antitumor efficacy of CAR-T cells. However, due to the fact that acquired resistance to checkpoint inhibitors will occur in most patients, it is vital to investigate other strategies to further improve the antitumor efficacy of CAR-T cell therapy in solid tumors. Recently, CD40 agonist antibodies have been shown to possess potential antitumor efficacy by activating the CD40 pathway.ResultsBased on the piggyBac transposon system, rather than the widely used viral vector, we constructed a meso3-CD40 CAR-T targeting region III of mesothelin (MSLN) that possesses the ability to secrete anti-CD40 antibodies. The results show that compared with meso3 CAR-T, which does not secrete the anti-CD40 antibody, meso3-CD40 CAR-T secreted more cytokines and had a relatively higher proportion of central memory T (TCM) cells after being stimulated by the target antigen. In addition, compared with meso3 CAR-T, we found that meso3-CD40 CAR-T had a more powerful cytotoxicity effect on target cells at a relatively low effector to target ratio. More importantly, we demonstrated that meso3-CD40 CAR-T also had enhanced antitumor activity in a human ovarian cancer xenograft in vivo.ConclusionsIn conclusion, these results showed that anti-CD40-secreting CAR-T cells generated by non-viral vectors could be a potential clinical strategy for improving the efficacy of CAR-T cell therapies.

Immunotherapy use in kidney transplant recipients: Immune checkpoint inhibitors and CAR-T cell therapy

2020 ◽  
Vol 4 (3) ◽  
pp. 165-170
Author(s):  
Claude Bassil ◽  
Farhad Khimani
Keyword(s):  
T Cell ◽  
Renal Transplant ◽  
Acute Rejection ◽  
Cell Therapy ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Transplant Recipients ◽  
T Cell Therapy ◽  
Car T

Cancer immunotherapy including the use of immune checkpoint inhibitors (ICI) and chimeric antigen receptor T cell therapy (CAR-T) are showing a promising role as part of cancer therapy and slowly replacing conventional chemotherapy. However, the use of ICI and CAR-T in organ transplant recipients with malignancies could be complicated with acute rejection and graft loss. Many proposed immunosuppressive (IS) regimens showed a probable role in preventing acute rejection related to ICI, including the use of a single ICI rather than double ICI, concomitant use of glucocorticoids (GC), converting tacrolimus to mTor inhibitors (m-TorI) and avoid close sequencing of ICI agents. Furthermore, low dose prednisone (LDP) before CAR-T infusion in patients with stable allograft kidney function could favor the regulatory T cells (T-regs), actively regulating alloimmune responses, and maintaining self-tolerance of the renal transplant. Further prospective trials will be needed to examine the long-term effect of these regimens in renal transplant recipients undergoing CAR-T or receiving ICI as curative therapies for their refractory cancers.

scholarly journals Combination Strategies for Immune-Checkpoint Blockade and Response Prediction by Artificial Intelligence

2020 ◽  
Vol 21 (8) ◽  
pp. 2856 ◽  
Author(s):  
Florian Huemer ◽  
Michael Leisch ◽  
Roland Geisberger ◽  
Thomas Melchardt ◽  
Gabriel Rinnerthaler ◽  
...  
Keyword(s):  
Artificial Intelligence ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
Immune Checkpoint ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Combination Strategies ◽  
Car T Cell Therapy ◽  
Car T

The therapeutic concept of unleashing a pre-existing immune response against the tumor by the application of immune-checkpoint inhibitors (ICI) has resulted in long-term survival in advanced cancer patient subgroups. However, the majority of patients do not benefit from single-agent ICI and therefore new combination strategies are eagerly necessitated. In addition to conventional chemotherapy, kinase inhibitors as well as tumor-specific vaccinations are extensively investigated in combination with ICI to augment therapy responses. An unprecedented clinical outcome with chimeric antigen receptor (CAR-)T cell therapy has led to the approval for relapsed/refractory diffuse large B cell lymphoma and B cell acute lymphoblastic leukemia whereas response rates in solid tumors are unsatisfactory. Immune-checkpoints negatively impact CAR-T cell therapy in hematologic and solid malignancies and as a consequence provide a therapeutic target to overcome resistance. Established biomarkers such as programmed death ligand 1 (PD-L1) and tumor mutational burden (TMB) help to select patients who will benefit most from ICI, however, biomarker negativity does not exclude responses. Investigating alterations in the antigen presenting pathway as well as radiomics have the potential to determine tumor immunogenicity and response to ICI. Within this review we summarize the literature about specific combination partners for ICI and the applicability of artificial intelligence to predict ICI therapy responses.

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