Adoptive transfer of neoantigen-specific T-cell therapy is feasible in older patients with higher-risk myelodysplastic syndrome

Tanaka, Tiffany; Ferrari, Valentina; Tarke, Alison; Fields, Hannah; Ferrari, Luca; Ferrari, Franco; McCarthy, Christopher; Sanchez, Amber P.; Vitiello, Antonella; Lane, Thomas A.; Bejar, Rafael

doi:10.1016/j.jcyt.2020.11.003

Cited by 7 publications

(7 citation statements)

References 17 publications

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“…These findings have direct relevance on the use of ICI in combination with ACT in MDS and suggest that blocking PD-1:PD-L1 would provide little or no benefit in a combination therapy. Given the efficacy of MDS cell lysis by neoantigen-specific T cells, our results suggest that ACT should be considered in combination with lymphodepletion and interleukin expansion strategies (5).…”

Section: Discussionmentioning

confidence: 91%

“…Personalized therapy by adoptive cell transfer (ACT) of autologous T cells specific for MDS tumor cell neoantigens is an attractive new approach to treat MDS patients (4,5). A potential drawback to this approach is the induction of PD-1 on the surface of tumor-specific T cells and the presence of PD-L1 on tumor targets, resulting in inhibitory interactions that suppress T-cell responses.…”

Section: Introductionmentioning

confidence: 99%

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Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing

Ferrari¹,

Tarke²,

Fields³

et al. 2022

Front. Oncol.

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The PD-1:PD-L1 axis is a binary interaction that delivers inhibitory signals to T cells, impeding both immune surveillance and response to immunotherapy. Here we analyzed a phenomenon whereby tumor-specific T cells induce PD-L1 upregulation in autologous MDS cells in short-term culture, through a mechanism that is cell-contact-independent and partially IFNγ-dependent. After investigating a panel of small-molecule inhibitors, we determined that PD-L1 upregulation was attributed to the PKR-like ER kinase (PERK) branch of the unfolded protein response. Interestingly, we found that the cytotoxic capacity of tumor-specific T cells was not impaired by the expression of PD-L1 on MDS target cells. These results highlight a little appreciated aspect of PD-1:PD-L1 regulation in hematologic cancers and indicate that this phenomenon, while likely to hinder autochthonous immune surveillance, may not be an obstacle to immunotherapies such as personalized adoptive T-cell therapy.

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Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing

Ferrari¹,

Tarke²,

Fields³

et al. 2022

Front. Oncol.

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“…The presence of WT1-specific CD8 + T cells is observed in the BM of MDS patients [ 108 ]. Phase I clinical trials of vaccination with WT1 are safe and well tolerated and demonstrate the induction of a tumor-specific CD8 + T-cell response in MDS patients [ 109 , 110 ]. Similarly, vaccination of MDS patients with the NY-ESO-1 tumor antigen induces a tumor-specific CD8 + T-cell response [ 111 ].…”

Section: Abnormal Immune Cell Repartition And/or Functions During The...mentioning

confidence: 99%

“…Phase I clinical trials demonstrate that neoantigen-specific CD8 + T cells from MDS patients can be expanded in vitro and are capable of killing autologous tumor cells [ 112 ]. Infusion of these neoantigen-specific CD8 + T cells into MDS patients is safe and well tolerated [ 109 ]. Overall, these data demonstrate that MDS patients could be good candidates for immunotherapies targeting CD8 + T cells, but treatment efficacy could be improved by the identification of appropriate therapeutic targets (e.g., tumor antigens shared by a group of patients) and a better delineation of the patient subgroups.…”

Section: Abnormal Immune Cell Repartition And/or Functions During The...mentioning

confidence: 99%

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

Simoni

Chapuis

2022

Diagnostics

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Myelodysplastic syndromes (MDS) constitute a very heterogeneous group of diseases with a high prevalence in elderly patients and a propensity for progression to acute myeloid leukemia. The complexity of these hematopoietic malignancies is revealed by the multiple recurrent somatic mutations involved in MDS pathogenesis and the paradoxical common phenotype observed in these patients characterized by ineffective hematopoiesis and cytopenia. In the context of population aging, the incidence of MDS will strongly increase in the future. Thus, precise diagnosis and evaluation of the progression risk of these diseases are imperative to adapt the treatment. Dysregulations of both innate and adaptive immune systems are frequently detected in MDS patients, and their critical role in MDS pathogenesis is now commonly accepted. However, different immune dysregulations and/or dysfunctions can be dynamically observed during the course of the disease. Monitoring the immune system therefore represents a new attractive tool for a more precise characterization of MDS at diagnosis and for identifying patients who may benefit from immunotherapy. We review here the current knowledge of the critical role of immune dysfunctions in both MDS and MDS precursor conditions and discuss the opportunities offered by the detection of these dysregulations for patient stratification.

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“…Chimeric antigen receptor (CAR) T-cell therapy targeting CD123 successfully eliminated MDS stem cells both in vitro and in patient-derived xenografts [162]. Bispecific CD3/CD123 or CD3/CD33 antibodies [154,162,163] as well as personalized adoptive cell therapy, which selects, immunizes and expands T-cells against MDS-specific mutations and targets patient-specific tumor cell neo-antigens, may be promising [164]. Diagnosis, prognosis and implications for treatment should be discussed in multidisciplinary boards composed by hemato-oncologists, hematopathologists, radiologist, human geneticists, molecular biologists, clinical pharmacologist, infectiologists, psycho-oncologist, nutritionists and nurses.…”

Section: Higher-risk Mdsmentioning

confidence: 99%

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Chanias

Stojkov

Stehle

et al. 2021

Cancers

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Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

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Adoptive transfer of neoantigen-specific T-cell therapy is feasible in older patients with higher-risk myelodysplastic syndrome

Cited by 7 publications

References 17 publications

Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing

Tumor-specific T cell-mediated upregulation of PD-L1 in myelodysplastic syndrome cells does not affect T-cell killing

Diagnosis of Myelodysplastic Syndromes: From Immunological Observations to Clinical Applications

Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

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