The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

Xia, Leiming; Wang, Yi; Li, Tan; Hu, Xiaofang; Chen, Qian; Liu, Liu; Jiang, Beilei; Li, Caixin; Wang, Hua; Wang, Siying; Yang, Guanghua; Bao, Yongzhan

doi:10.1002/cam4.2193

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…The first attempts of RS treatment with this approach were conducted few years ago in 2 patients with poor responses, including disease progression [65] and evolution to plasmablastic lymphoma [66]. Additional studies performed in relapsed patients who underwent hematopoietic stem cell transplantation and chemo-immunotherapy showed only partial responses [67,68].…”

Section: Chimeric Antigen Receptor T-cell Therapy (Car-t)mentioning

confidence: 99%

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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Opinion statementIn the last 10–15 years, the way to treat cancers has dramatically changed towards precision medicine approaches. These treatment options are mainly based on selective targeting against signaling pathways critical for or detrimentally activated in cancer cells in cancer cells, as well as exploiting molecules that are specifically expressed on neoplastic cells, also known as tumor-associated antigens. These considerations hold true also in the hematological field where a plethora of novel targeted agents have reached patients’ bedside, significantly improving clinical responses. Chronic lymphocytic leukemia (CLL) is an example of how targeted therapies, such as BTK, PI3K, or Bcl-2 inhibitors as well as anti-CD20 antibodies, have improved patients’ management, even when adopted as frontline treatment. However, these advancements do not apply to Richter’s syndrome (RS), the transformation of CLL into a very aggressive and fatal lymphoma, occurring in 2–10% of patients. RS is usually a fast-growing lymphoma of the diffuse large B cell or the Hodgkin’s variant, with a dismal prognosis. Despite advancements in depicting and understanding the genetic background of RS and its pathogenesis, no significant clinical results have been registered. In the last couple of years, several studies have started to investigate the impact of novel drugs or drug combinations and some of them have opened for clinical trials, currently in phase I or II, whose results will be soon available. This review will present an overview of current and most recent therapeutic options in RS, discussing also how results coming from xenograft models may help in designing and identifying novel treatment opportunities to overcome the lack of effective therapies.

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Section: Chimeric Antigen Receptor T-cell Therapy (Car-t)mentioning

confidence: 99%

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Iannello

Deaglio

Vaisitti

2022

Curr. Treat. Options in Oncol.

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“…Here we report our experience with 118 CD19 CAR T products. CAR T cells were mainly produced from patients with ALL and non-Hodgkin's lymphoma (NHL), but also from patients with r/r Richter's transformation and CD19 positive acute myeloid leukemia (AML) (10,(14)(15)(16). We compared the potency and proliferation capacity of CAR T cells initiated from cryopreserved versus fresh leukapheresis products and the antitumor reactivity of cryopreserved versus fresh infusion products.…”

Section: Introductionmentioning

confidence: 99%

Impact of cryopreservation on CAR T production and clinical response

et al. 2022

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Adoptive cell therapy with chimeric antigen receptor (CAR) T cells has become an efficient treatment option for patients with hematological malignancies. FDA approved CAR T products are manufactured in centralized facilities from fresh or frozen leukapheresis and the cryopreserved CAR T infusion product is shipped back to the patient. An increasing number of clinical centers produce CAR T cells on-site, which enables the use of fresh and cryopreserved PBMCs and CAR T cells. Here we determined the effect of cryopreservation on PBMCs and CD19 CAR T cells in a cohort of 118 patients treated with fresh CAR T cells and in several patients head-to-head. Cryopreserved PBMCs, obtained from leukapheresis products, contained less erythrocytes and T cells, but were sufficient to produce CAR T cells for therapy. There was no correlation between the recovery of PBMCs and the transduction efficacy, the number of CAR T cells obtained by the end of the manufacturing process, the in vitro reactivity, or the response rate to CAR T therapy. We could show that CAR T cells cryopreserved during the manufacturing process, stored and resumed expansion at a later time point, yielded sufficient cell numbers for treatment and led to complete remissions. Phenotype analysis including T cell subtypes, chemokine receptor and co-inhibitory/stimulatory molecules, revealed that fresh CAR T cells expressed significantly more TIM-3 and contained less effector T cells in comparison to their frozen counterparts. In addition, fresh CAR T infusion products demonstrated increased in vitro anti-tumor reactivity, however cryopreserved CAR T cells still showed high anti-tumor potency and specificity. The recovery of cryopreserved CAR T cells was similar in responding and non-responding patients. Although fresh CAR T infusion products exhibit higher anti-tumor reactivity, the use of frozen PBMCs as staring material and frozen CAR T infusion products seems a viable option, as frozen products still exhibit high in vitro potency and cryopreservation did not seem to affect the clinical outcome.

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Synergistic efficacy of the dual PI3K-δ/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models

Iannello

Vitale

Coma

et al. 2021

Blood

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A small subset of cases of chronic lymphocytic leukemia undergoes transformation to diffuse large B-cell lymphoma, Richter's Syndrome (RS), which is associated with a poor prognosis. Conventional chemotherapy results in limited responses, underlining the need for novel therapeutic strategies. Here, we investigate the ex-vivo and in vivo efficacy of the dual PI3K-d/g inhibitor Duvelisib (Duv) and the Bcl-2 inhibitor Venetoclax (Ven) using four different RS-patient-derived xenograft (PDX) models. Ex-vivo exposure of RS cells to Duv, Ven or their combination results in variable apoptotic responses, in line with the expression levels of target proteins. While RS1316, IP867/17 and RS9737 cells express PI3K-d, PI3K-g and Bcl-2 and respond to the drugs, RS1050 cells, expressing very low levels of PI3K-g and lacking Bcl-2, are fully resistant. Moreover, the combination of these drugs is more effective than each agent alone. When tested in vivo, RS1316 and IP867/17 show the best tumor growth inhibition responses, with Duv/Ven combination leading to complete remission at the end of treatment. The synergistic effect of Duv and Ven relies on the crosstalk between PI3K and apoptotic pathways occurring at the GSK3β level. Indeed, inhibition of PI3K signaling by Duv results in GSK3β activation, leading to ubiquitination and subsequent degradation of both c-Myc and Mcl-1, making RS cells more sensitive to Bcl-2 inhibition by Ven. This work provides, for the first time, a proof-of-concept of the efficacy of dual targeting of PI3K-d/g and Bcl-2 in RS, opening for a Duv/Ven combination for these patients. Clinical studies in aggressive lymphomas, including RS, are underway (NCT03892044).

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The clinical study on treatment of CD19‐directed chimeric antigen receptor‐modified T cells in a case of refractory Richter syndrome

Cited by 3 publications

References 27 publications

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Novel Approaches for the Treatment of Patients with Richter’s Syndrome

Impact of cryopreservation on CAR T production and clinical response

Synergistic efficacy of the dual PI3K-δ/γ inhibitor duvelisib with the Bcl-2 inhibitor venetoclax in Richter syndrome PDX models

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