Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma

Background: Multiple myeloma (MM) is a plasma cell disorder and demonstrates overexpression of B cell maturation antigen (BCMA). Our objective is to evaluate the safety and efficacy of chimeric antigen receptor T cells (CAR-T) against BCMA in patients with relapsed/refractory multiple myeloma (RRMM). Methods: We conducted a systematic literature search using PubMed, Cochrane, Clinicaltrials.gov, and Embase databases. We also searched for data from society meetings. A total of 935 articles were identified, and 610 were screened for relevance. Results: Data from thirty-one original studies with a total of 871 patients (pts) were included based on defined eligibility criteria, see Table 1. Hu et al. reported an overall response rate (ORR) of 100% in 33 pts treated with BCMA CAR-T cells including 21 complete response (CR), 7 very good partial response (VGPR), 4 partial response (PR). Moreover, 32 pts achieved minimal residual disease (MRD) negative status. Chen et al. reported ORR of 88%, 14% CR, 6% VGPR, and 82% MRD negative status with BCMA CAR-T therapy in 17 RRMM pts. In another clinical trial by Han et al. BCMA CAR-T therapy demonstrated an ORR of 100% among 7 evaluable pts with 43% pts having ≥ CR and 14% VGPR. An ORR of 100% with 64% stringent CR (sCR) and 36% VGPR was reported with novel anti-BCMA CART cells (CT103A). Similarly, Li et al. reported ORR of 87.5%, sCR of 50%, VGPR 12.5%, and PR 25% in 16 pts. BCMA targeting agent, JNJ-4528, showed ORR of 91%, including 4sCR, 2CR, 10MRD, and 7VGPR. CAR-T- bb2121 demonstrated ORR of 85%, sCR 36%, CR 9%, VGPR 57%, and MRD negativity of 100% (among 16 responsive pts). GSK2857916, a BCMA targeting CAR-T cells yielded ORR of 60% in both clinical trials. Three studies utilizing bispecific CART cells targeting both BCMA & CD38 (LCARB38M) reported by Zhao et al., Wang et al., and Fan et al. showed ORR of 88%, 88%, & 100% respectively. Topp et al. reported ORR of 31% along with 5 ≥CR and 5 MRD negative status in 42 pts treated with Bi T-cells Engager BiTE® Ab BCMA targeting antigen (AMG420). One clinical trial presented AUTO2 CART cells therapy against BCMA with an ORR of 43%, VGPR of 14%, and PR of 28%. CT053CAR-BCMA showed 14sCR and 5CR with a collective ORR of 87.5% and MRD negative status of 85% in 24 and 20 evaluable pts, respectively. Likewise, Mikkilineni et al. reported an ORR of 83%, sCR of 16.7%, and VGPR & PR of 25% and 41% in 12 pts treated with FHVH-BCMA T cells. Similar results are also reported in other clinical trials of BCMA targeting CART therapy (Table 1). The most common adverse effects exhibited were grade 1-3 hematologic (cytopenia) and cytokine release syndrome (CRS) (mostly reversible with tocilizumab). Conclusion: Initial data from ongoing clinical trials using BCMA targeting CAR-T therapy have yielded promising results both in terms of improved outcome and tolerable toxicity profiles. Although two phase 3 trails are ongoing, additional data is warranted to further ensure the safety and efficacy of anti-BCMA CAR-T cells therapy in pts with RRMM for future use. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

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CAR T cells targeting options in the fight against multiple myeloma

Panminerva Medica ◽

10.23736/s0031-0808.20.04146-4 ◽

2021 ◽

Vol 63 (1) ◽

Author(s):

Fabio NICOLINI ◽

Sara BRAVACCINI ◽

Massimiliano MAZZA ◽

Alicja M. GRUSZKA ◽

Marcella TAZZARI ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Car T Cells ◽

Car T

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CD229 CAR T cells eliminate multiple myeloma and tumor propagating cells without fratricide

Nature Communications ◽

10.1038/s41467-020-14619-z ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 8

Author(s):

Sabarinath V. Radhakrishnan ◽

Tim Luetkens ◽

Sandra D. Scherer ◽

Patricia Davis ◽

Erica R. Vander Mause ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

Car T Cells ◽

Car T

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GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells

Science Translational Medicine ◽

10.1126/scitranslmed.aau7746 ◽

2019 ◽

Vol 11 (485) ◽

pp. eaau7746 ◽

Cited By ~ 49

Author(s):

Eric L. Smith ◽

Kim Harrington ◽

Mette Staehr ◽

Reed Masakayan ◽

Jon Jones ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Cell Therapy ◽

B Cell ◽

T Cell Therapy ◽

Car T Cells ◽

Car T Cell Therapy ◽

Car T

Early clinical results of chimeric antigen receptor (CAR) T cell therapy targeting B cell maturation antigen (BCMA) for multiple myeloma (MM) appear promising, but relapses associated with residual low-to-negative BCMA-expressing MM cells have been reported, necessitating identification of additional targets. The orphan G protein–coupled receptor, class C group 5 member D (GPRC5D), normally expressed only in the hair follicle, was previously identified as expressed by mRNA in marrow aspirates from patients with MM, but confirmation of protein expression remained elusive. Using quantitative immunofluorescence, we determined that GPRC5D protein is expressed on CD138+ MM cells from primary marrow samples with a distribution that was similar to, but independent of, BCMA. Panning a human B cell–derived phage display library identified seven GPRC5D-specific single-chain variable fragments (scFvs). Incorporation of these into multiple CAR formats yielded 42 different constructs, which were screened for antigen-specific and antigen-independent (tonic) signaling using a Nur77-based reporter system. Nur77 reporter screen results were confirmed in vivo using a marrow-tropic MM xenograft in mice. CAR T cells incorporating GPRC5D-targeted scFv clone 109 eradicated MM and enabled long-term survival, including in a BCMA antigen escape model. GPRC5D(109) is specific for GPRC5D and resulted in MM cell line and primary MM cytotoxicity, cytokine release, and in vivo activity comparable to anti-BCMA CAR T cells. Murine and cynomolgus cross-reactive CAR T cells did not cause alopecia or other signs of GPRC5D-mediated toxicity in these species. Thus, GPRC5D(109) CAR T cell therapy shows potential for the treatment of advanced MM irrespective of previous BCMA-targeted therapy.

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Hematologic Malignancies: Plasma Cell Disorders

American Society of Clinical Oncology Educational Book ◽

10.1200/edbk_175546 ◽

2017 ◽

pp. 561-568 ◽

Cited By ~ 1

Author(s):

Madhav V. Dhodapkar ◽

Ivan Borrello ◽

Adam D. Cohen ◽

Edward A. Stadtmauer

Keyword(s):

Bone Marrow ◽

T Cells ◽

Monoclonal Antibodies ◽

T Cell ◽

Cell Surface ◽

Plasma Cell ◽

Antigen Specificity ◽

Immune Effector ◽

Car T Cells ◽

Car T

Multiple myeloma (MM) is a plasma cell malignancy characterized by the growth of tumor cells in the bone marrow. Properties of the tumor microenvironment provide both potential tumor-promoting and tumor-restricting properties. Targeting underlying immune triggers for evolution of tumors as well as direct attack of malignant plasma cells is an emerging focus of therapy for MM. The monoclonal antibodies daratumumab and elotuzumab, which target the plasma cell surface proteins CD38 and SLAMF7/CS1, respectively, particularly when used in combination with immunomodulatory agents and proteasome inhibitors, have resulted in high response rates and improved survival for patients with relapsed and refractory MM. A number of other monoclonal antibodies are in various stages of clinical development, including those targeting MM cell surface antigens, the bone marrow microenvironment, and immune effector T cells such as antiprogrammed cell death protein 1 antibodies. Bispecific preparations seek to simultaneously target MM cells and activate endogenous T cells to enhance efficacy. Cellular immunotherapy seeks to overcome the limitations of the endogenous antimyeloma immune response through adoptive transfer of immune effector cells with MM specificity. Allogeneic donor lymphocyte infusion can be effective but can cause graft-versus-host disease. The most promising approach appears to be genetically modified cellular therapy, in which T cells are given novel antigen specificity through expression of transgenic T-cell receptors (TCRs) or chimeric antigen receptors (CARs). CAR T cells against several different targets are under investigation in MM. Infusion of CD19-targeted CAR T cells following salvage autologous stem cell transplantation (SCT) was safe and extended remission duration in a subset of patients with relapsed/refractory MM. CAR T cells targeting B-cell maturation antigen (BCMA) appear most promising, with dramatic remissions seen in patients with highly refractory disease in three ongoing trials. Responses are associated with degree of CAR T-cell expansion/persistence and often toxicity, including cytokine release syndrome (CRS) and neurotoxicity. Ongoing and future studies are exploring correlates of response, ways to mitigate toxicity, and “universal” CAR T cells.

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Clinical Responses In Patients Infused With T Lymphocytes Redirected To Target κ-Light Immunoglobulin Chain

Blood ◽

10.1182/blood.v122.21.506.506 ◽

2013 ◽

Vol 122 (21) ◽

pp. 506-506 ◽

Cited By ~ 6

Author(s):

Carlos A. Ramos ◽

Barbara Savoldo ◽

Enli Liu ◽

Adrian P. Gee ◽

Zhuyong Mei ◽

...

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

B Cell ◽

Light Chain ◽

Stable Disease ◽

Research Funding ◽

B Cell Malignancies ◽

Car T Cells ◽

Car T

Abstract Adoptive transfer of T cells with a CD19-specific chimeric antigen receptor (CAR) to treat B-cell malignancies shows remarkable clinical efficacy. However, long-term persistence of T cells targeting CD19, a pan-B cell marker, causes sustained depletion of normal B cells and consequent severe hypogammaglobulinemia. In order to target B-cell malignancies more selectively, we exploited the clonal restriction of mature B-cell malignancies, which express either a κ or a λ-light immunoglobulin (Ig) chain. We generated a CAR specific for κ-light chain (CAR.κ) to selectively target κ+ lymphoma/leukemia cells, while sparing the normal B cells expressing the reciprocal λ-light chain, thus minimizing the impairment of humoral immunity. After preclinical validation, we designed a phase I clinical trial in which patients with refractory/relapsed κ+ non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL) are infused with autologous T cells expressing a CAR.κ that includes a CD28 costimulatory domain. The protocol also included patients with multiple myeloma with the aim of targeting putative myeloma initiating cells. Three dose levels (DL) are being assessed, with escalation determined by a continual reassessment method: 0.2 (DL1), 1 (DL2) and 2 (DL3) ×108 T cells/m2. Repeat infusions are allowed if there is at least stable disease after treatment. End points being evaluated include safety, persistence of CAR+T cells and antitumor activity. T cells were generated for 13 patients by activating autologous PBMC with immobilized OKT3 (n=5) or CD3/CD28 monoclonal antibodies (n=8). In 2 patients with >95% circulating leukemic cells, CD3 positive selection was performed using CliniMACS. After transduction, T cells (1.2×107±0.5×107) were expanded ex vivo for 18±4 days in the presence of interleukin (IL)-2 to reach sufficient numbers for dose escalation. CAR expression was 81%±13% by flow cytometry (74,112±23,000 transgene copy numbers/mg DNA). Products were composed predominantly of CD8+ cells (78%±10%), with a small proportion of naïve (5±4%) and memory T cells (17%±12%). CAR+ T cells specifically targeted κ+ tumors as assessed by 51Cr release assays (specific lysis 79%±10%, 20:1 E:T ratio) but not κ–tumors (11%±7%) or the NK-sensitive cell line K562 (26%±13%). Ten patients have been treated: 2 on DL1, 3 on DL2 and 5 on DL3. Any other treatments were discontinued at least 4 weeks prior to T-cell infusion. Patients with an absolute leukocyte count >500/µL received 12.5 mg/kg cyclophosphamide 4 days before T-cell infusion to induce mild lymphopenia. Infusions were well tolerated, without side effects. Persistence of infused T cells was assessed in blood by CAR.κ-specific Q-PCR assay and peaked 1 to 2 weeks post infusion, remaining detectable for 6 weeks to 9 months. Although the CAR contained a murine single-chain variable fragment (scFv), we did not detect human anti-mouse antibodies following treatment and CAR.κ+T cell expansion continued to be observed even after repeated infusions. We detected modest (<20 fold) elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells, but systemic inflammatory response syndrome (cytokine storm) was absent. No new-onset hypogammaglobulinemia was observed. All 10 patients are currently evaluable for clinical response. Of the patients with relapsed NHL, 2/5 entered complete remission (after 2 and 3 infusions at dose level 1 and 3, respectively), 1/5 had a partial response and 2 progressed; 3/3 patients with multiple myeloma have had stable disease for 2, 8 and 11 months, associated with up to 38% reduction in their paraprotein; and 2/2 patients with CLL progressed before or shortly after the 6-week evaluation. In conclusion, our data indicate that infusion of CAR.κ+ T cells is safe at every DL and can be effective in patients with κ+ lymphoproliferative disorders. Disclosures: Savoldo: Celgene: Patents & Royalties, Research Funding. Rooney:Celgene: Patents & Royalties, Research Funding. Heslop:Celgene: Patents & Royalties, Research Funding. Brenner:Celgene: Patents & Royalties, Research Funding. Dotti:Celgene: Patents & Royalties, Research Funding.

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