Sequential CD19 and BCMA‐specific CAR T‐cell treatment elicits sustained remission of relapsed and/or refractory myeloma

Yan, Litao; Qu, Su; Shang, Jingjing; Shi, Xiaolan; Kang, Liqing; Xu, Nan; Zhu, Mingqing; Zhou, Jin; Jin, Song; Yao, Weiqin; Yao, Ying; Chen, Guanghua; Chang, Huirong; Zhu, Xiaofan; Yu, Lei; Wu, Depei; Fu, Chengcheng

doi:10.1002/cam4.3624

Cited by 40 publications

(51 citation statements)

References 27 publications

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“…Similarly, ex vivo treatment of MM cells with a mixture of both CD19 CAR T cells and BCMA CAR T cells was more effective in reducing colony formation capability than either CD19 CAR T cells or BCMA CAR T cells alone (38,46). Several clinical studies in patients with RRMM have demonstrated a high response rate with the combination of CD19-and BCMA-targeting CAR T cells (47)(48)(49). On-target/off-tumor toxicity consisted of B-cell aplasia and hypogammaglobulinemia (47).…”

Section: Tumor-related Resistance Mechanisms (Soluble) Bcmamentioning

confidence: 99%

“…For example, CD38-specific CAR T cells or BCMA/CD38 dual-targeted CAR T cells have the ability to eliminate CD38 + immune suppressor cells, such as regulatory B cells (Breg), in patients with MM (50,132). Bregs were also eradicated by CD19-specific CAR T cells (49). Furthermore, in the face of Treg-mediated inhibition, superior functionality of CD28 over 4-1BB signaling was reported, which is possibly explained through enhanced secretion of proinflammatory cytokines in the presence of Tregs by CD28-based CAR T cells (123).…”

Section: Immune Resistance Conferred By the Tumor Microenvironmentmentioning

confidence: 99%

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Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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B-cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T cells have substantial therapeutic potential in multiple myeloma (MM), but most patients eventually relapse. Determinants of response and mechanisms of resistance are most likely multifactorial and include MM-related factors, premanufacturing T-cell characteristics, CAR T-cell-related features, and several components of the immunosuppressive microenvironment. Efforts to improve the potency and safety of CAR T-cell therapy include optimizing CAR design, combinatorial approaches to enhance persistence and activity, treatment of less heavily pretreated patients, and dual-antigen targeting to prevent antigen escape. We expect that these rationally designed strategies will contribute to further improvement in the clinical outcome of patients with MM.Significance: Although BCMA-specific CAR T-cell therapies are highly effective in heavily pretreated patients with MM, there has been, until now, no indication of a plateau in the survival curves. In this review, we provide an overview of the determinants of response and the mechanisms that contribute to the development of treatment failure after initial remission (acquired resistance). A better understanding of these mechanisms, underlying lack of disease response, and acquired resistance may lead to further improvements in the effectiveness of CAR T-cell therapy. iNtRODUctiONAlthough the introduction of new anti-multiple myeloma (MM) agents has markedly improved the survival of patients with MM, there is an unmet need for new drugs for patients who develop resistance to immunomodulatory drugs (IMiD), proteasome inhibitors (PI), and CD38-targeting antibodies (triple-class refractory disease), which carries a poor prognosis (1). Also, newly diagnosed patients with high-risk disease [e.g., presence of del(17p), t(4;14), or t(14;16)] or suboptimal response have an impaired outcome, and these patients may benefit from the incorporation of new drugs with novel mechanisms of action in first-line regimens.A promising new strategy is the reprogramming of T cells to target MM cells by introducing genes encoding chimeric antigen receptors (CAR). CARs are fusion proteins, combining an antigen-recognition moiety [commonly a monoclonal antibody-derived single-chain variable fragment (scFv), but other formats such as natural ligands are also possible; ref.2] with a T-cell activation domain, typically CD3ζ. These two parts are connected via an extracellular spacer region (hinge) and a transmembrane-spanning element. Second-generation CARs incorporating a costimulatory domain, such as CD28, 4-1BB, OX40, or ICOS, into the CAR endodomain result in enhanced antitumor activity of the modified T cells compared with first-generation CARs without such domain (Fig. 1; ref. 3). Importantly, CAR T cells eliminate tumor cells in a non-major histocompatibility complex (MHC)restricted manner.Most CAR T-cell products, currently evaluated in clinical trials for patients with MM, target B-cell maturation antigen (BCMA), which is...

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Section: Tumor-related Resistance Mechanisms (Soluble) Bcmamentioning

confidence: 99%

Section: Immune Resistance Conferred By the Tumor Microenvironmentmentioning

confidence: 99%

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Donk

Themeli

Usmani

2021

Blood Cancer Discovery

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“…The combination of a CAR-T against BCMA with another CAR-T against CD19 has already been explored in early clinical trials. 70 The development of bi-specific CAR-Ts may be even more effective to prevent disease progression associated to loss of BCMA expression. Bicistronic vectors encoding two CARs avoid the challenge of parallel manufacturing separate CAR-T-cell products, while providing superior efficacy.…”

Section: Future Perspectivesmentioning

confidence: 99%

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Oriol

Abril

Torrent

et al. 2021

Therapeutic Advances in Hematology

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The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

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“…Finally, the desire of some patients to reduce their pill burden, prompting them to take their medication only when symptoms appear, should be taken into account when aiming to improve treatment adherence. In this respect, NEPA is the only fixed combination of an NK 1 RA and a 5-HT3RA and has the simplest administration schedule [ 41 ], offering a highly convenient method of administration for most patients. Simple administration schedules would not only facilitate adherence by physicians, but could also prevent patients from making medication errors, a recurring problem during home administration in the delayed phase.…”

Section: Discussionmentioning

confidence: 99%

Prevention of chemotherapy-induced nausea and vomiting in the real-world setting in Spain

et al. 2021

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Purpose Proper monitoring and management of chemotherapy-induced nausea and vomiting (CINV) with antiemetics is crucial for cancer patients. This study aimed to evaluate the use of antiemetics for the treatment of highly emetogenic chemotherapy (HEC) including carboplatin in the real-world setting in Spain. Methods A representative panel of cancer specialists was asked to collect information about the antiemetic treatments provided to patients receiving chemotherapy. Records formed part of the Global Oncology Monitor© database (Ipsos Healthcare, London, UK). Chemotherapy data were extrapolated using Ipsos Healthcare’s projection methodology. Results A total of 73 experts were finally included. Data from 9519 patients, estimated to be representative of 202,084 patients, were collected. HEC (and carboplatin-based chemotherapy) was administered to 73,118 (36%) patients, cisplatin-based therapy being the most frequent treatment (n = 34,649, 47.38%). Neurokinin-1 receptor antagonists (NK1RAs) alone or in combination were used as prophylaxis for CINV in 14,762 (20%) patients, while the combination of NK1RA with 5-hydroxytryptamine-3 receptor antagonist (5-HT3RAs) and dexamethasone as recommended by the international guidelines was used in 5849 (8%) patients only. No antiemetic prophylaxis was administered to 8.46% of the patients receiving HEC (n = 6189). Physicians classified cisplatin-, anthracycline-cyclophosphamide (AC-), and carboplatin-based regimens as HEC in 63%, 22% and 4% of the cases, respectively. Conclusions The use of NK1RA-containing regimens for CINV prevention in patients treated with HEC was less than expected, suggesting poor adherence to international antiemetic guidelines.

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Sequential CD19 and BCMA‐specific CAR T‐cell treatment elicits sustained remission of relapsed and/or refractory myeloma

Cited by 40 publications

References 27 publications

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

Determinants of Response and Mechanisms of Resistance of CAR T-cell Therapy in Multiple Myeloma

The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

Prevention of chemotherapy-induced nausea and vomiting in the real-world setting in Spain

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