Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia

Hasanali, Zainul; Saroya, Bikramajit Singh; Stuart, August; Shimko, Sara; Evans, Juanita J.; Shah, Mithun Vinod; Sharma, Kamal; Leshchenko, Violetta V.; Parekh, Samir; Loughran, Thomas P.; Epner, Elliot

doi:10.1126/scitranslmed.aaa5079

Cited by 47 publications

(39 citation statements)

References 60 publications

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“…Importantly, HDAC inhibitors (vorinostat, belinostat, romidepsin) are FDA approved for the treatment of nodal and cutaneous peripheral T cell lymphomas (PTCL, CTCL). In a series of eight relapsed T-PLL patients, the combination of HDAC inhibitors with cladribine, a purine analog with epigenetic activity, enhanced the anti-leukemic activity of alemtuzumab and overcame previous treatment resistance towards this antibody as shown by responses in all treated patients (7 of 8 achieved a CR) [52]. Furthermore, an induction of CD30 expression after treatment with this combination was reported therein.…”

Section: Epigenetic Modulationmentioning

confidence: 82%

Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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Purpose of Review T cell prolymphocytic leukemia (T-PLL) is a rare mature T cell tumor. Available treatment options in this aggressive disease are largely inefficient and patient outcomes are highly dissatisfactory. Current therapeutic strategies mainly employ the CD52-antibody alemtuzumab as the most active single agent. However, sustained remissions after sole alemtuzumabbased induction are exceptions. Responses after available second-line strategies are even less durable. More profound disease control or rare curative outcomes can currently only be expected after a consolidating allogeneic hematopoietic stem cell transplantation (allo-HSCT) in best first response. However, only 30-50% of patients are eligible for this procedure. Major advances in the molecular characterization of T-PLL during recent years have stimulated translational studies on potential vulnerabilities of the T-PLL cell. We summarize here the current state of "classical" treatments and critically appraise novel (pre)clinical strategies. Recent Findings Alemtuzumab-induced first remissions, accomplished in ≈ 90% of patients, last at median ≈ 12 months. Series on allo-HSCT in T-PLL, although of very heterogeneous character, suggest a slight improvement in outcomes among transplanted patients within the past decade. Dual-action nucleosides such as bendamustine or cladribine show moderate clinical activity as single agents in the setting of relapsed or refractory disease. Induction of apoptosis via reactivation of p53 (e.g., by inhibitors of HDAC or MDM2) and targeting of its downstream pathways (i.e., BCL2 family antagonists, CDK inhibitors) are promising new approaches. Novel strategies also focus on inhibition of the JAK/STAT pathway with the first clinical data. Implementations of immune-checkpoint blockades or CART cell therapy are at the stage of pre-clinical assessments of activity and feasibility. Summary The recommended treatment strategy in T-PLL remains a successful induction by infusional alemtuzumab followed by a consolidating allo-HSCT in eligible patients. Nevertheless, long-term survivors after this "standard" comprise only 10-20%. The increasingly revealed molecular make-up of T-PLL and the tremendous expansion of approved targeted compounds in oncology represent a "never-before" opportunity to successfully tackle the voids in T-PLL. Approaches, e.g., those reinstating deficient cell death execution, show encouraging pre-clinical and first-inhuman results in T-PLL, and urgently have to be transferred to systematic clinical testing.

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Section: Epigenetic Modulationmentioning

confidence: 82%

Advances and Perspectives in the Treatment of T-PLL

Braun

Jan

Wahnschaffe

et al. 2020

Curr Hematol Malig Rep

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“…In T‐prolymphocytic leukaemia (T‐PLL), treatment with cladribine has been shown to induce CD30 expression, enabling successful use of anti‐CD30 directed therapy. This phenomenon appeared to be T‐PLL specific and was not appreciated in MCL (Hasanali et al , ). However, it does suggest that cladribine has the potential to modify the expression of potential therapeutic targets.…”

Section: Discussionmentioning

confidence: 99%

Phase 1–2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B‐cell non‐Hodgkin lymphoma and previously untreated mantle cell lymphoma

et al. 2019

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Summary Altered DNA methylation and histone acetylation in lymphoma provided the rationale for using vorinostat (SAHA), cladribine and rituximab (SCR) in non‐Hodgkin lymphomas (NHL) in this phase 1–2 study (NCT00764517). Treatment included cladribine 5 mg/m2 intravenously (IV) (days 1–5), rituximab 375 mg/m2 IV (weekly 4× for cycle 1 and 1×/month) and vorinostat orally once daily (days 1–14) every 28 days for up to six cycles. Phase 1 included relapsed patients (n = 10) in a standard 3 + 3 dose escalation design (vorinostat: 200, 300 and 400 mg). No dose‐limiting toxicities were seen. The phase 2 dose for vorinostat was 400 mg po (days 1–14). The majority of phase 2 patients had mantle cell lymphoma (MCL) (n = 57; 39 previously untreated, 10 relapsed). The primary objective was objective response rate [complete response (CR) + partial response] which was 39% (7/18) in relapsed patients and 97% (38/39) with 80% (31/39) attaining a CR in previously untreated MCL. At a median follow‐up of 42 months, median progression‐free survival (PFS) and overall survival (OS) for relapsed NHL were 19·5 [95% confidence interval (CI): 2·0–33·0] and 25·0 (95% CI: 12·0–45·0) months respectively. Median PFS for previously untreated MCL was 84·0 months; OS could not be estimated. Toxicities were primarily haematological.

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“…Likewise, preclinical in vivo work has suggested that restoration of MHC-I expression by modulation of epigenetic markers, such as inhibitors of DNA methyltransferase (DNMT) or histone deacetylase (HDAC), constitutes an attractive approach to be used as a complement to TCR-modified T cell administration for successful tumour eradication [126][127][128] , even in the context of cancers that are resistant to immune checkpoint blockade 129 . A few clinical trials have been performed evaluating the effects of combining epigenetic modulation with vaccine/antibody/cytokine-based immunotherapy, which rendered promising results [130][131][132] . However, the feasibility/benefit of this approach in the context of clinical ACT using remains to be determined.…”

Section: Mhc-i Downregulationmentioning

confidence: 99%

T-cell receptor gene-modified cells: past promises, present methodologies and future challenges

Rego

Morris²,

Lowdell

2019

Cytotherapy

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Immunotherapy constitutes an exciting and rapidly evolving field, and the demonstration that genetically-modified T cell receptors (TCRs) can be used to produce T lymphocyte populations of desired specificity offers new opportunities for antigen-specific T cell therapy.Overall, TCR-modified T cells have the ability to target a wide variety of self and non-self targets through the normal biology of a T cell. Although MHC-restricted and dependent on co-receptors, genetically engineered TCRs still present a number of characteristics that ensure they are an important alternative strategy to chimeric antigen receptors (CARs), and high affinity TCRs can now be successfully engineered with the potential to enhance therapeutic efficacy while minimising adverse events.This review will focus on the main characteristics of TCR gene-modified cells, their potential clinical application and promise to the field of adoptive cell transfer (ACT), basic manufacturing procedures and characterisation protocols, and overall challenges that need to be overcome so that redirection of TCR specificity may be successfully translated into clinical practice, beyond early phase clinical trials. BackgroundWith roots in the principles of basic immunology, synthetic biology and genetic engineering, the field of adoptive cell transfer (ACT) has become one of the most promising and innovative approaches to treat cancer, viral infections and other immune-modulated diseases.There are currently three main types of ACT using effector T cells 1 : administration of tumour infiltrating lymphocytes (TILs), and gene transfer-based strategies relying on genetic engineering to express either chimeric antigen (Ag) receptors (CARs) -composed of antibody (Ab)-binding domains fused to T cell signalling domains -or engineered T cell receptor (TCR) α/β heterodimers.Genetic modification of autologous T cells to target specific tumour antigens has been developed to overcome the consequences of immune tolerance and offers the possibility to endow the immune system with reactivities not naturally present. This approach has the additional benefit of rapid tumour eradication, which is usually observed with cytotoxic chemotherapy or other targeted therapies rather than the delayed responses that are commonly observed with vaccines and T cell checkpoint therapies. Page 2 of 33Durable anticancer responses have been extensively reported for CARs targeting CD19 in the treatment of acute lymphoblastic leukaemia (ALL), B-cell lymphomas 2 and chronic lymphocytic leukaemia (CLL), and the US Food and Drug Administration (FDA) has recently approved two genetically engineered CD19 CAR T cell products, tisagenlecleucel (Kymriah) 3 and axicabtagene ciloleucel (Yescarta) 4 , for clinical application. Therapeutic TCR gene-modified T cells have demonstrated clinical activity in earlier phase clinical trials but their development currently lags behind CAR T cells 2 . The unique biology of TCR-peptide/MHC recognition may render TCR-modified T cells a more suitable approach for specific t...

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Epigenetic therapy overcomes treatment resistance in T cell prolymphocytic leukemia

Cited by 47 publications

References 60 publications

Advances and Perspectives in the Treatment of T-PLL

Advances and Perspectives in the Treatment of T-PLL

Phase 1–2 study of vorinostat (SAHA), cladribine and rituximab (SCR) in relapsed B‐cell non‐Hodgkin lymphoma and previously untreated mantle cell lymphoma

T-cell receptor gene-modified cells: past promises, present methodologies and future challenges

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