Overcoming Antigen Escape with CAR T-cell Therapy

Jackson, Hollie J.; Brentjens, Renier J.

doi:10.1158/2159-8290.cd-15-1275

Cited by 74 publications

(57 citation statements)

References 13 publications

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“…While strategies to understand antigen escape mechanisms and to increase rates of long term remission are developed 134 , allo HSCT can reasonably be considered for patients with Table 3 | CAR T cell-related encephalopathy syndrome grading and management…”

Section: Car T Cell Therapy As a Bridge To Hsctmentioning

confidence: 99%

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

et al. 2018

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In 2017, an autologous chimeric antigen receptor (CAR) T cell therapy indicated for children and young adults with relapsed and/or refractory CD19 acute lymphoblastic leukaemia became the first gene therapy to be approved in the USA. This innovative form of cellular immunotherapy has been associated with remarkable response rates but is also associated with unique and often severe toxicities, which can lead to rapid cardiorespiratory and/or neurological deterioration. Multidisciplinary medical vigilance and the requisite health-care infrastructure are imperative to ensuring optimal patient outcomes, especially as these therapies transition from research protocols to standard care. Herein, authors representing the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network Hematopoietic Stem Cell Transplantation (HSCT) Subgroup and the MD Anderson Cancer Center CAR T Cell Therapy-Associated Toxicity (CARTOX) Program have collaborated to provide comprehensive consensus guidelines on the care of children receiving CAR T cell therapy.

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Section: Car T Cell Therapy As a Bridge To Hsctmentioning

confidence: 99%

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

et al. 2018

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“…A proportion of the relapsed patients experience antigen-negative disease recurrence, manifested by the outgrowth of CD19 À tumor cells. 58,59 This phenomenon therefore highlights the important subject of tumor antigen heterogeneity, even when the target antigen is uniformly expressed on all tumor cells. Investigation into the mechanisms leading to this antigen loss phenomenon revealed an alternative splicing mechanism of the CD19 mRNA, resulting in the loss of the cognate epitope on the CD19 protein required for recognition by CD19-CAR T cells.…”

Section: Inducing Tumor Eradication Beyond Car T-cell Antigen Recognimentioning

confidence: 88%

“…59 One strategy to potentially promote tumor killing beyond a CAR T-cell antigen-specific response has been through further modification of these cells to secrete proinflammatory cytokines (Figure 1). Indeed, engagement of endogenous cellular immunity has been reported to induce antigennegative tumor cell killing following antigenspecific T-cell therapy.…”

Section: Inducing Tumor Eradication Beyond Car T-cell Antigen Recognimentioning

confidence: 99%

“…Indeed, engagement of endogenous cellular immunity has been reported to induce antigennegative tumor cell killing following antigenspecific T-cell therapy. 59 One strategy to potentially promote tumor killing beyond a CAR T-cell antigen-specific response has been through further modification of these cells to secrete proinflammatory cytokines (Figure 1). A study by Chmielewski et al elegantly demonstrated the capacity of CAR T cells engineered to secrete the IL-12 cytokine that enabled responses against both antigen-positive and antigen-negative tumor cells.…”

Section: Inducing Tumor Eradication Beyond Car T-cell Antigen Recognimentioning

confidence: 99%

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Switching on the green light for chimeric antigen receptor T‐cell therapy

et al. 2019

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Adoptive cellular therapy involving genetic modification of T cells with chimeric antigen receptor (CAR) transgene offers a promising strategy to broaden the efficacy of this approach for the effective treatment of cancer. Although remarkable antitumor responses have been observed following CAR T‐cell therapy in a subset of B‐cell malignancies, this has yet to be extended in the context of solid cancers. A number of promising strategies involving reprogramming the tumor microenvironment, increasing the specificity and safety of gene‐modified T cells and harnessing the endogenous immune response have been tested in preclinical models that may have a significant impact in patients with solid cancers. This review will discuss these exciting new developments and the challenges that must be overcome to deliver a more sustained and potent therapeutic response.

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“…58 Several further strategies may be incorporated into future studies to address the problem of antigen escape in B cell malignancies, including modification of CAR T cells to target multiple tumor associated antigens, administration of checkpoint inhibitors, and as discussed in the next section, introduction of additional genetic manipulations to autologous T cells to overcome inhibitory features of the tumor microenvironment. 59 Additionally, the use of CAR T cells targeting the immunoglobulin superfamily member CD22, expressed on mature and some immature B cells, is currently being investigated in relapsed CD22 + B-ALL and other CD22 + B cell malignancies, including but not restricted to patients with CD19-negative relapse following CD19-targeted CAR T cell therapy (NCT02650414, NCT02315612).…”

Section: Challenges In Current Clinical Use Of Car T Cellsmentioning

confidence: 99%

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells

Geyer

Brentjens

2016

Cytotherapy

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The past several years have been marked by extraordinary advances in clinical applications of immunotherapy. In particular, adoptive cellular therapy utilizing chimeric antigen receptor (CAR) modified T cells targeted to CD19 has demonstrated substantial clinical efficacy in children and adults with relapsed or refractory B cell acute lymphoblastic leukemia (B-ALL), and durable clinical benefit in a smaller subset of patients with relapsed or refractory chronic lymphocytic leukemia (CLL) or B cell non-Hodgkin lymphoma (B-NHL). Early phase clinical trials are presently assessing CAR T cell safety and efficacy in additional malignancies. Herein, we discuss clinical results from the largest series to date investigating CD19-targeted CAR T cells in B-ALL, CLL, and B-NHL, including discussion of differences in CAR T cell design and production and treatment approach, as well as clinical efficacy, nature of severe cytokine release syndrome and neurologic toxicities, and CAR T cell expansion and persistence. We additionally review the current and forthcoming use of CAR T cells in multiple myeloma and several solid tumors, and highlight challenges and opportunities afforded by the current state of CAR T cell therapies, including strategies to overcome inhibitory aspects of the tumor microenvironment and enhance antitumor efficacy.

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Overcoming Antigen Escape with CAR T-cell Therapy

Abstract: Summary Sotillo and colleagues describe the molecular events associated with apparent loss of target antigen expression following CAR T-cell therapy. We propose that broader immune activation is required to prevent outgrowth of tumor antigen escape variants following targeted therapies.

Cited by 74 publications

References 13 publications

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy

Switching on the green light for chimeric antigen receptor T‐cell therapy

Review: Current clinical applications of chimeric antigen receptor (CAR) modified T cells

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