Personal tumor antigens in blood malignancies: genomics-directed identification and targeting

Penter, Livius; Wu, Catherine J.

doi:10.1172/jci129209

Cited by 12 publications

(10 citation statements)

References 187 publications

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“…The whole movie demonstrates that T cells are able to recognize and kill the tumor cells (Falchi & Lapenta, unpublished observations) recognize and bind to cancer cells, causing their death. These findings corroborate the feasibility of the anti-cancer therapeutic approach by exploiting patient-derived instructed cytotoxic T cells, a promising strategy of exploiting vaccinal approach for cancer (Penter & Wu, 2020). This intrinsically simple experimental set may be helpful to devise new therapies, since it is also suitable for studying the modulatory effects of drugs and cytokines, as well as investigating the mechanisms that regulate interactions between tumor cells and T cells, for example, by means of fluorescent antibodies against intercellular adhesion molecules.…”

Section: Manipulations Of the Subject During Observationsupporting

confidence: 77%

Evolution and new frontiers of histology in bio‐medical research

Mazzarini

Falchi

Bani

et al. 2020

Microscopy Res & Technique

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Histology refers to the study of the morphology of cells within their natural tissue environment. As a bio-medical discipline, it dates back to the development of first microscopes which allowed to override the physical visual limitation of the human eye. Since the first observations, it was understood that cell shape predicts function and, therefore, shape alterations can identify and explain dysfunction and diseases. The advancements in morphological investigation techniques have allowed to extend our understanding of the shape-function relationships close to the molecular level of organization of tissues, as well as to derive reliable data not only from fixed, and hence static, biological samples but also living cells and tissues and even for extended time periods. These modern approaches, which encompass quantitative microscopy, precision microscopy, and dynamic microscopy, represent the new frontier of morphology. This article summarizes how the microscopy techniques have evolved to properly face the challenges of biomedical sciences, thus transforming histology from a merely qualitative discipline, which played an ancillary role to traditional "major" sciences such as anatomy, to a modern experimental science capable of driving knowledge progress in biology and medicine.

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Section: Manipulations Of the Subject During Observationsupporting

confidence: 77%

Evolution and new frontiers of histology in bio‐medical research

Mazzarini

Falchi

Bani

et al. 2020

Microscopy Res & Technique

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“…1 Immunotherapies that reinstate the graft-versus-leukemia (GvL) effect may be efficacious in this setting. 2 Indeed, the observed overexpression of PD-L1 in JAK2 V617F+ mutated acute myeloid leukemia (AML) provided an immunologic basis for use of off-label PD-1 blockade in an index case of relapsed JAK2 V617F+ secondary AML post-HSCT who experienced transient response but acquired subsequent resistance. 3 While the sensitivity to PD-1 blockade is uncommon among myeloid malignancies 4 , the course of this patient afforded an opportunity to deeply examine the co-evolving kinetics of heterogeneous leukemic and immune cell populations after therapy.…”

Section: Introductionmentioning

confidence: 99%

Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case

Penter¹,

Gohil

Huang³

et al. 2021

Blood Advances

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Relapse of myeloproliferative neoplasms (MPN) after allogeneic hematopoietic stem cell transplantation (HSCT) is associated with poor outcomes, as therapeutic approaches to reinstate effective graft-versus-leukemia (GvL) responses remain suboptimal. Immune escape through overexpression of PD-L1 in JAK2V617F mutated MPN provides a rationale for therapeutic PD-1 blockade, and indeed clinical activity of nivolumab in relapsed MPN post-HSCT has been observed. Elucidation of the features of response following PD-1 blockade in such patients could inform of novel therapeutic concepts for how to enhance GvL. Here, we report an integrated high-dimensional analysis using single cell RNA-, TCR-, CITE- and ATAC-sequencing together with mass cytometry on peripheral blood mononuclear cells collected at 6 timepoints before, during and after transient response to PD-1 blockade from an index case of relapsed MPN following HSCT. Before nivolumab infusion, AML blasts demonstrated high expression of chemokines, and T cells were characterized by expression of interferon-response genes. This baseline inflammatory signature disappeared after nivolumab infusion. Clinical response was characterized by transient expansion of a polyclonal CD4+ T cell population and contraction of an AML subpopulation that exhibited megakaryocytic features and elevated PD-L1 expression. At relapse, the proportion of the AML subpopulation with progenitor-like features progressively increased, suggesting co-evolution of AML blasts and donor-derived T cells. We thus demonstrate how single cell technologies can provide complementary insight into cellular mechanisms underlying response to PD-1 blockade, motivating future longitudinal high-dimensional single cell studies of GvL responses in relapsed myeloid disease.

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“…1 Immune escape mechanisms contribute to relapse post-HSCT 2 and suggest a reinvigorated graft-versus-leukemia (GVL) effect could improve outcomes. 3 Indeed, the Experimental Therapeutics Clinical Trials Network 9204 trial demonstrated that immune checkpoint blockade (ICB) can induce regression of relapsed AML after HSCT through CD8 1 T-cell recruitment to leukemic sites. 4,5 Through unbiased molecular profiling of the leukemic microenvironment and peripheral blood immunophenotyping of samples from study subjects on this trial, we sought to elucidate the molecular and cellular features of immunologic responses to ICB.…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

Penter

Zhang

Savell

et al. 2021

Blood

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Relapsed myeloid disease after allogeneic stem cell transplantation (HSCT) remains largely incurable. We previously demonstrated the potent activity of immune checkpoint blockade (ICB) in this clinical setting with ipilimumab or nivolumab. To define the molecular and cellular pathways by which CTLA-4 blockade with ipilimumab can reinvigorate an effective graft-versus-leukemia (GvL) response, we integrated transcriptomic analysis of leukemic biopsies with immunophenotypic profiling of matched peripheral blood samples collected from patients treated with ipilimumab following HSCT on the ETCTN 9204 trial. Response to ipilimumab was associated with transcriptomic evidence of increased local CD8+ T cell infiltration and activation. Systemically, ipilimumab decreased naïve and increased memory T cell populations and increased expression of markers of T cell activation and co-stimulation such as PD-1, HLA-DR and ICOS, irrespective of response. However, responding patients were characterized by higher turnover of T cell receptor sequences in peripheral blood and showed increased expression of proinflammatory chemokines in plasma that was further amplified by ipilimumab. Altogether, these data highlight the compositional T cell shifts and inflammatory pathways induced by ipilimumab both locally and systemically that associate with successful GvL outcomes.

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Personal tumor antigens in blood malignancies: genomics-directed identification and targeting

Abstract: Conflict of interest:CJW is a cofounder of Neon Therapeutics and is a member of its scientific advisory board.

Cited by 12 publications

References 187 publications

Evolution and new frontiers of histology in bio‐medical research

Evolution and new frontiers of histology in bio‐medical research

Coevolving JAK2V617F+relapsed AML and donor T cells with PD-1 blockade after stem cell transplantation: an index case

Molecular and cellular features of CTLA-4 blockade for relapsed myeloid malignancies after transplantation

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