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Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

ABSTRACT: Chimeric antigen receptor (CAR)-T cells have demonstrated significant improvements in the treatment of refractory B-cell malignancies that previously showed limited survival. In contrast, early-phase clinical studies targeting solid tumors have been disappointing. This may be due to both a lack of specific and homogeneously expressed targets at the surface of tumor cells, as well as intrinsic properties of the solid tumor microenvironment that limit homing and activation of adoptive T cells. Faced with these antagonistic conditions, radiotherapy (RT) has the potential to change the overall tumor landscape, from depleting tumor cells to reshaping the tumor microenvironment. In this article, we describe the current landscape and discuss how RT may play a pivotal role for enhancing the efficacy of adoptive T-cell therapies in solid tumors. Indeed, by improving homing, expansion and activation of infused T cells while reducing tumor volume and heterogeneity, the use of RT could help the implementation of engineered T cells in the treatment of solid tumors.

SUBMITTER: Laurent PA

PROVIDER: S-EPMC9788698 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

Laurent Pierre-Antoine PA Morel Daphne D Meziani Lydia L Depil Stephane S Deutsch Eric E

Oncoimmunology 20221222 1

Chimeric antigen receptor (CAR)-T cells have demonstrated significant improvements in the treatment of refractory B-cell malignancies that previously showed limited survival. In contrast, early-phase clinical studies targeting solid tumors have been disappointing. This may be due to both a lack of specific and homogeneously expressed targets at the surface of tumor cells, as well as intrinsic properties of the solid tumor microenvironment that limit homing and activation of adoptive T cells. Fac ...[more]

PMID: 36567802

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Project description:The incidence of brain metastases of solid tumors is increasing. Local treatment of brain metastases is generally straightforward: cranial radiotherapy (e.g., whole-brain radiotherapy or stereotactic radiosurgery) or resection when feasible. However, treatment becomes more complex when brain metastases occur while other metastases, outside of the central nervous system, are being controlled with systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies). It is known that some anticancer agents can increase the risk for neurotoxicity when used concurrently with radiotherapy. Increased neurotoxicity decreases quality of life, which is undesirable in this predominantly palliative patient group. Therefore, it is of utmost importance to identify the compounds that should be temporarily discontinued when cranial radiotherapy is needed.This review summarizes the (neuro)toxicity data for combining systemic therapy (chemotherapeutics, molecular targeted agents, or monoclonal antibodies) with concurrent radiotherapy of brain metastases. Because only a limited amount of high-level data has been published, a risk assessment of each agent was done, taking into account the characteristics of each compound (e.g., lipophilicity) and the microenvironment of brain metastasis. The available trials suggest that only gemcitabine, erlotinib, and vemurafenib induce significant neurotoxicity when used concurrently with cranial radiotherapy. We conclude that for most systemic therapies, the currently available literature does not show an increase in neurotoxicity when these therapies are used concurrently with cranial radiotherapy. However, further studies are needed to confirm safety because there is no high-level evidence to permit definitive conclusions. The Oncologist 2017;22:222-235Implications for Practice: The treatment of symptomatic brain metastases diagnosed while patients are receiving systemic therapy continues to pose a dilemma to clinicians. Will concurrent treatment with cranial radiotherapy and systemic therapy (chemotherapeutics, molecular targeted agents, and monoclonal antibodies), used to control intra- and extracranial tumor load, increase the risk for neurotoxicity? This review addresses this clinically relevant question and evaluates the toxicity of combining systemic therapies with cranial radiotherapy, based on currently available literature, in order to determine the need to and interval to interrupt systemic treatment.

Project description:BackgroundThe triple combination of programmed cell death 1 (PD1)/programmed cell death ligand 1 (PDL1) inhibitors, radiotherapy (RT), and anti-angiogenesis agents has been widely used in the treatment of solid tumors and has shown positive efficacy. We conducted a meta-analysis to evaluate the efficacy and safety of PD1/PDL1 inhibitors combined with anti-angiogenic agents and RT for the treatment of solid cancers.MethodsA systematic search of PubMed, Embase, Cochrane Library, and Web of Science databases was conducted from inception to October 31, 2022. Studies involving patients with solid cancers who received PD1/PDL1 inhibitors combined with RT and anti-angiogenic agents treatment that reported overall response rate, complete remission rate, disease control rate, and adverse events (AEs) were included. A random-effects or fixed-effects model was used for the pooled rates, and 95% confidence intervals (CIs) were determined for all outcomes. The quality of the included literature was assessed using the methodological index for nonrandomized studies critical appraisal checklist. Egger test was used to assess the publication bias in the included studies.ResultsTen studies (4 nonrandomized controlled trials and 6 single-arm trials), including 365 patients, were identified and included in the meta-analysis. The pooled overall response rate after treatment with PD1/PDL1 inhibitors combined with RT and anti-angiogenic agents was 59% (95% CI: 48-70%), whereas the disease control rate and complete remission rate were 92% (95% CI: 81-103%) and 48% (95% CI: 35-61%), respectively. Moreover, the meta-analysis showed that compared with triple-regimen, monotherapy or dual-combination treatment did not improve overall survival (hazard ratio = 0.499, 95% CI: 0.399-0.734) and progression-free survival (hazard ratio = 0.522, 95% CI: 0.352-0.774). The pooled rate of grade 3 to 4 AEs was 26.9% (95% CI: 7.8%-45.9), and the common AEs to triple therapy included leukopenia (25%), thrombocytopenia (23.8%), fatigue (23.2%), gastrointestinal discomfort (22%), increased alanine aminotransferase (22%), and neutropenia (21.4%).ConclusionIn the treatment of solid tumors, PD1/PDL1 inhibitors combined with RT and anti-angiogenic drugs achieved a positive response and better survival benefits than monotherapy or dual therapy. In addition, combination therapy is tolerable and safe.RegistrationPROSPERO ID: CRD42022371433.

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Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

Publications

Radiotherapy as a means to increase the efficacy of T-cell therapy in solid tumors.

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