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European Journal of Cancer (Oxford,... Nov 2023Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT).... (Review)
Review
Immunotherapy has ignited hope to cure paediatric solid tumours that resist traditional therapies. Among the most promising methods is adoptive cell therapy (ACT). Particularly, ACT using T cells equipped with chimeric antigen receptors (CARs) has moved into the spotlight in clinical studies. However, the efficacy of ACT is challenged by ACT-intrinsic factors, like lack of activation or T cell exhaustion, as well as immune evasion strategies of paediatric solid tumours, such as their highly immunosuppressive microenvironment. Novel strategies, including ACT using innate-like lymphocytes, innovative cell engineering techniques, and ACT combination therapies, are being developed and will be crucial to overcome these challenges. Here, we discuss the main classes of ACT for the treatment of paediatric extracranial solid tumours, reflect on the available preclinical and clinical evidence supporting promising strategies, and address the challenges that ACT is still facing. Ultimately, we highlight state-of-the-art developments and opportunities for new therapeutic options, which hold great potential for improving outcomes in this challenging patient population.
Topics: Humans; Child; Immunotherapy, Adoptive; Neoplasms; T-Lymphocytes; Receptors, Chimeric Antigen; Immunotherapy; Tumor Microenvironment
PubMed: 37832507
DOI: 10.1016/j.ejca.2023.113347 -
International Journal of Molecular... Jun 2021Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several... (Review)
Review
Immunotherapy is now considered an innovative and strong strategy to beat metastatic, drug-resistant, or relapsing tumours. It is based on the manipulation of several mechanisms involved in the complex interplay between cancer cells and immune system that culminates in a form of immune-tolerance of tumour cells, favouring their expansion. Current immunotherapies are devoted enforcing the immune response against cancer cells and are represented by approaches employing vaccines, monoclonal antibodies, interleukins, checkpoint inhibitors, and chimeric antigen receptor (CAR)-T cells. Despite the undoubted potency of these treatments in some malignancies, many issues are being investigated to amplify the potential of application and to avoid side effects. In this review, we discuss how sphingolipids are involved in interactions between cancer cells and the immune system and how knowledge in this topic could be employed to enhance the efficacy of different immunotherapy approaches. In particular, we explore the following aspects: how sphingolipids are pivotal components of plasma membranes and could modulate the functionality of surface receptors expressed also by immune cells and thus their functionality; how sphingolipids are related to the release of bioactive mediators, sphingosine 1-phosphate, and ceramide that could significantly affect lymphocyte egress and migration toward the tumour milieu, in addition regulating key pathways needed to activate immune cells; given the renowned capability of altering sphingolipid expression and metabolism shown by cancer cells, how it is possible to employ sphingolipids as antigen targets.
Topics: Animals; Antigens, Neoplasm; Cell Communication; Disease Management; Disease Susceptibility; Humans; Immune System; Immunomodulation; Immunotherapy; Immunotherapy, Adoptive; Lysophospholipids; Neoplasms; Signal Transduction; Sphingolipids; Sphingosine; Treatment Outcome
PubMed: 34204326
DOI: 10.3390/ijms22126492 -
PloS One 2013Metastatic renal cell carcinoma (mRCC), as one of the most immunogenic tumors has been the focus of adoptive cellular immunotherapy (ACI), but the effects of ACI on... (Meta-Analysis)
Meta-Analysis Review
PURPOSE
Metastatic renal cell carcinoma (mRCC), as one of the most immunogenic tumors has been the focus of adoptive cellular immunotherapy (ACI), but the effects of ACI on objective response and survival in patients with mRCC are still controversial. Therefore, a systematic review and meta-analysis was performed to address this issue.
METHODS
A search was conducted in the PubMed database for randomized clinical trials (RCTs) with ACI in mRCC. All included articles in this study were assessed according to the selection criteria and were divided into two groups: ACI versus no ACI. Outcomes were toxicity, objective response, 1-, 3- and 5-year survival. Risk ratio (RR) and 95% confidence intervals (CI) were calculated using a fixed-effects meta-analysis. Heterogeneity was measured by value of I(2) or P.
RESULTS
4 studies (469 patients) were included. Most of ACI-related adverse reactions were grade 1 or 2 and reversible. ACI provided significant benefit in terms of objective response (RR = 1.65; 95% CI, 1.15 to 2.38; P = 0.007, I(2) = 49%), 1-year survival (RR = 1.30; 95% CI, 1.12 to 1.52; P = 0.0008, I(2) = 0%), 3-year survival (RR = 2.76; 95% CI, 1.85 to 4.14; P<0.00001, I(2) = 46%) and 5-year survival (RR = 2.42; 95% CI, 1.21 to 4.83; P = 0.01, I(2) = 28%).
CONCLUSIONS
ACI may be a safe and effective treatment for improving objective response, 1-, 3- and 5-year survival in patients with mRCC. Besides, five obstacles for ACI, including high degree of personalization, unsuitable WHO/RECIST response criteria, inadequate identification of tumor-associated antigens (TAAs), lack of effective combination treatments and less attention paid to the quality of ACI products, should be overcome during the successful development of more potent ACI for cancer in the future.
Topics: Carcinoma, Renal Cell; Humans; Immunotherapy, Adoptive; Kidney Neoplasms; Neoplasm Metastasis; Survival Analysis; Treatment Outcome
PubMed: 23667530
DOI: 10.1371/journal.pone.0062847 -
British Journal of Haematology Mar 2017In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of... (Review)
Review
In vitro discoveries have paved the way for bench-to-bedside translation in adoptive T cell immunotherapy, resulting in remarkable clinical responses in a variety of haematological malignancies. Adoptively transferred T cells genetically modified to express CD19 CARs have shown great promise, although many unanswered questions regarding how to optimize T-cell therapies for both safety and efficacy remain. Similarly, T cells that recognize viral or tumour antigens though their native receptors have produced encouraging clinical responses. Honing manufacturing processes will increase the availability of T-cell products, while combining T-cell therapies has the ability to increase complete response rates. Lastly, innovative mechanisms to control these therapies may improve safety profiles while genome editing offers the prospect of modulating T-cell function. This review will focus on recent advances in T-cell immunotherapy, highlighting both clinical and pre-clinical advances, as well as exploring what the future holds.
Topics: Antigens, CD19; Hematologic Neoplasms; Humans; Immunotherapy; Immunotherapy, Adoptive; T-Lymphocytes
PubMed: 27897332
DOI: 10.1111/bjh.14470 -
The Journal of Surgical Research Apr 2014Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid... (Review)
Review
Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid tumors. It is important for clinicians, especially surgeons, to understand the basic principles of novel immunotherapies and the immune system. This review summarizes the evolution of the most relevant immunotherapies, their mechanisms of action, the data supporting their clinical use, and integration of immunotherapy into multidisciplinary management of solid tumors. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of immunotherapy.
Topics: Cancer Vaccines; Combined Modality Therapy; General Surgery; Humans; Immunotherapy, Adoptive; Neoplasms
PubMed: 24485876
DOI: 10.1016/j.jss.2013.12.018 -
Current Problems in Cancer 2018Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are... (Review)
Review
Biliary tract cancers (BTC) are aggressive malignancies associated with resistance to chemotherapy and poor prognostic rates. Therefore, novel treatment approaches are in need. Immunotherapy represents a promising breakthrough that uses a patient's immune system to target a tumor. This treatment approach has shown immense progress with positive results for selected cancers such as melanoma and nonsmall cell lung cancer. Initial preclinical data and preliminary clinical studies suggest encouraging mechanistic effects for immunotherapy in BTC offering the hope for an expanding therapeutic role for this disease. These approaches include targeted tumor antigen therapy via peptide and dendritic cell-based vaccines, allogenic cell adoptive immunotherapy, and the use of inhibitory agents targeting the immune checkpoint receptor pathway and multiple components of the tumor microenvironment. At this time demonstrating efficacy in larger clinical trials remains imperative. A multitude of ongoing trials aim to successfully translate mechanistic effects into antitumor efficacy and ultimately aim to incorporate immunotherapy into the routine management of BTC. With further research efforts, the optimization of dosing and therapeutic regimens, the identification of novel tumor antigens and a better understanding of alternative checkpoint pathway receptor expression may provide additional targets for rational combinatorial therapies which enhance the effects of immunotherapy and may offer hope for further advancing treatment options. Ultimately, the challenge remains to prospectively identify the subsets of patients with BTC who may respond to immunotherapy, and devising alternative strategies to sensitize those that do not with the hopes of improving outcomes for all with this deadly disease.
Topics: Antineoplastic Agents, Immunological; Biliary Tract Neoplasms; Cancer Vaccines; Cell Cycle Checkpoints; Cholangiocarcinoma; Humans; Immunotherapy; Immunotherapy, Adoptive; Medical Oncology; Protein Kinase Inhibitors; T-Lymphocytes
PubMed: 29501212
DOI: 10.1016/j.currproblcancer.2017.10.004 -
Discovery Medicine Jan 2014Adoptive immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment modality for acute and chronic leukemias that has... (Review)
Review
Adoptive immunotherapy in the form of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a treatment modality for acute and chronic leukemias that has been in practice for several decades. Drawbacks to transplantation include toxicity from chemotherapy/radiation conditioning regimens, additional toxicity from graft versus host disease, and reliance on appropriate human leukocyte antigen matched donors. Newer modalities with increased specificity of donor cells to tumor cells in addition to therapies that do not require engraftment for anti-tumor effect reduce the risk of graft versus host disease and may create a more robust graft versus leukemia response. Without the need for engraftment, or at the very least in the absence of a 100% engraftment requirement, conditioning regimens may be minimized. Three methods of adoptive immunotherapy that may offer some of these advantages over traditional transplantation are donor lymphocyte infusions (DLI), chimeric antigen receptor modified T cells (CAR T cells), and cellular immunotherapy. DLIs and cellular therapy consist of transfusing T lymphocytes from the donor to recipient in an unmanipulated form. Alternatively, donor T lymphocytes can be modified with addition of chimeric antigen receptors for specific antigen directed killing of tumor cells. Significant responses and survival benefit have been reported with these modalities. Herein, we review the mechanisms for these newer adoptive immune therapies, clinical indications for their use, and potential future directions.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Leukemia; Models, Immunological; Transplantation, Homologous
PubMed: 24411697
DOI: No ID Found -
Current Treatment Options in Oncology Feb 2022The therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin... (Review)
Review
The therapeutic armamentarium has significantly expanded since the approval of various CD19-targeting chimeric antigen receptor T cell (CAR-T) therapies in non-Hodgkin lymphoma (NHL). These CAR-Ts are patient-specific and require a complex, resource, and time-consuming process. While this appears promising, autologous CAR-Ts are limited due to the lack of accessibility, manufacturing delays, and variable product quality. To overcome these, allogeneic (allo) CARs from healthy donors appear appealing. These can be immediately available as "off the shelf" ready-to-use products of standardized and superior quality exempt from the effects of an immunosuppressive tumor microenvironment and prior treatments, and potentially with lower healthcare utilization using industrialized scale production. Allogeneic CARs, however, are not devoid of complications and require genomic editing, especially with αβ T cells to avoid graft versus host disease (GvHD) and allo-rejection by the recipient's immune system. Tools for genomic editing such as TALEN and CRISPR provide promise to develop truly "off the shelf" universal CARs and further advance the field of cellular immunotherapy. Several allogeneic CARs are currently in early phase clinical trials, and preliminary data is encouraging. Longer follow-up is required to truly assess the feasibility and safety of these techniques in the patients. This review focuses on the strategies for developing allogeneic CARs along with cell sources and clinical experience thus far in lymphoma.
Topics: Antigens, CD19; Hematopoietic Stem Cell Transplantation; Humans; Immunotherapy, Adoptive; Lymphoma; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen; T-Lymphocytes; Tumor Microenvironment
PubMed: 35212892
DOI: 10.1007/s11864-021-00920-6 -
Current Allergy and Asthma Reports Jan 2017Primary immunodeficiency disorders (PID) are a group of inborn errors of immunity with a broad range of clinical severity but often associated with recurrent and serious... (Review)
Review
Primary immunodeficiency disorders (PID) are a group of inborn errors of immunity with a broad range of clinical severity but often associated with recurrent and serious infections. While hematopoietic stem cell transplantation (HSCT) can be curative for some forms of PID, chronic and/or refractory viral infections remain a cause of morbidity and mortality both before and after HSCT. Although antiviral pharmacologic agents exist for many viral pathogens, these are associated with significant costs and toxicities and may not be effective for increasingly drug-resistant pathogens. Thus, the emergence of adoptive immunotherapy with virus-specific T lymphocytes (VSTs) is an attractive option for addressing the underlying impaired T cell immunity in many PID patients. VSTs have been utilized for PID patients following HSCT in many prior phase I trials, and may potentially be beneficial before HSCT in patients with chronic viral infections. We review the various methods of generating VSTs, clinical experience using VSTs for PID patients, and current limitations as well as potential ways to broaden the clinical applicability of adoptive immunotherapy for PID patients.
Topics: Hematopoietic Stem Cell Transplantation; Humans; Immunologic Deficiency Syndromes; Immunotherapy, Adoptive; T-Lymphocytes; Transplantation Conditioning
PubMed: 28116637
DOI: 10.1007/s11882-017-0669-2 -
Frontiers in Immunology 2022Chimeric-antigen receptor (CAR) T-cell immunotherapy employs autologous-T cells modified with an antigen-specific CAR. Current CAR-T manufacturing processes tend to...
Chimeric-antigen receptor (CAR) T-cell immunotherapy employs autologous-T cells modified with an antigen-specific CAR. Current CAR-T manufacturing processes tend to yield products dominated by effector T cells and relatively small proportions of long-lived memory T cells. Those few cells are a so-called stem cell memory T (T) subset, which express naïve T-cell markers and are capable of self-renewal and oligopotent differentiation into effector phenotypes. Increasing the proportion of this subset may lead to more effective therapies by improving CAR-T persistence; however, there is currently no standardized protocol for the effective generation of CAR-T cells. Here we present a simplified protocol enabling efficient derivation of gene-modified T cells: Stimulation of naïve CD8+ T cells with only soluble anti-CD3 antibody and culture with IL-7 and IL-15 was sufficient for derivation of CD8+ T cells harboring T phenotypes and oligopotent capabilities. These expanded T cells were engineered with CARs targeting the HIV-1 envelope protein as well as the CD19 molecule and demonstrated effector activity both and in a xenograft mouse model. This simple protocol for the derivation of CAR-T cells may facilitate improved adoptive immunotherapy.
Topics: Animals; Antigens, CD19; CD8-Positive T-Lymphocytes; Humans; Immunotherapy, Adoptive; Mice; Receptors, Antigen, T-Cell; Receptors, Chimeric Antigen
PubMed: 35967430
DOI: 10.3389/fimmu.2022.877682