Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy

Gardner, Rebecca; Wu, David; Cherian, Sindhu; Fang, Min; Hanafi, Laïla Aïcha; Finney, Olivia; Smithers, Hannah; Jensen, Michael C.; Riddell, Stanley R.; Maloney, David G.; Turtle, Cameron J.

doi:10.1182/blood-2015-08-665547

Cited by 624 publications

(540 citation statements)

References 14 publications

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“…However, as seen in patients with leukemia who receive CD19 directed immunotherapy, antigen loss may prevent durable remissions (11,12). In this case, re-biopsy of the target lesions was instrumental in guiding further management.…”

Section: Sequential Loss Of Tumor Surface Antigens Following Chimericmentioning

confidence: 98%

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

et al. 2018

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Section: Sequential Loss Of Tumor Surface Antigens Following Chimericmentioning

confidence: 98%

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

et al. 2018

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“…4 In contrast, the adult patient who showed a myeloid shift after CD19 chimeric antigen receptor T therapy, although achieving complete remission, died of AML relapse. 20 The ALL-to-AML switch can also be induced by chemotherapy and is usually associated with poor outcome. 5 Acquisition of additional genetic events enhancing the self-renewal program may give rise to the occasional MLL-Af4 AML in our model and t(4;11) AML in patients.…”

Section: E+00mentioning

confidence: 99%

“…It was reported that 2 t(4;11) ALL patients displayed a myeloid shift after CD19-directed therapy. 4,20 These 2 patients then received myeloid-directed therapy followed by allogeneic HSC transplantation. One infant patient, whose myeloid lineage transition was triggered by blinatumomab, achieved complete remission and remained alive at the time of publication.…”

Section: E+00mentioning

confidence: 99%

The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment

Lin

Luo

Shrestha

et al. 2017

Blood

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• Full oncogenic activity of MLL-Af4 is facilitated by lymphoid commitment and is compromised in the myeloid cell context. • The CHD domain of Af4 is sufficient to confer the linkage between lymphoid lineage and leukemic transformation.Chromosome rearrangements involving the mixed-lineage leukemia gene (MLL) create MLL-fusion proteins, which could drive both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). The lineage decision of MLL-fusion leukemia is influenced by the fusion partner and microenvironment. To investigate the interplay of fusion proteins and microenvironment in lineage choice, we transplanted human hematopoietic stem and progenitor cells (HSPCs) expressing MLL-AF9 or MLL-Af4 into immunodeficient NSGS mice, which strongly promote myeloid development. Cells expressing MLL-AF9 efficiently developed AML in NSGS mice. In contrast, MLL-Af4 cells, which were fully oncogenic under lymphoid conditions present in NSG mice, displayed compromised transformation capacity in a myeloid microenvironment. MLL-Af4 activated a self-renewal program in a lineage-dependent manner, showing the leukemogenic activity of MLL-Af4 was interlinked with lymphoid lineage commitment. The C-terminal homology domain (CHD) of Af4 was sufficient to confer this linkage. Although the MLL-CHD fusion protein failed to immortalize HSPCs in myeloid conditions in vitro, it could successfully induce ALL in NSG mice. Our data suggest that defective self-renewal ability and leukemogenesis of MLL-Af4 myeloid cells could contribute to the strong B-cell ALL association of MLL-AF4 leukemia observed in the clinic. (Blood. 2017;130(7):903-907)

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“…15,25 Attempts to translate recent achievements of cellular therapy with e.g., chimeric antigen receptor T cells into the treatment of solid tumors, in particular pediatric sarcomas, has had limited success so far. [9][10][11]26,27 Since oncogenic drivers often are not antigenic, additional targets selectively overexpressed and required for malignancy and metastasis are to be identified supporting the application of TCR driven T cells. 15,28,29 CHM1 is directly upregulated by the ES driving fusion oncogene EWS-FLI1 and maintains an undifferentiated, invasive phenotype, and metastatic spread.…”

Section: Discussionmentioning

confidence: 99%

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

et al. 2017

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Background: Chondromodulin-I (CHM1) sustains malignancy in Ewing sarcoma (ES). Refractory ES carries a dismal prognosis and patients with bone marrow (BM) metastases do not survive irrespective of therapy. We assessed HLA-A Ã 02:01/CHM1-specific allorestricted T cell receptor (TCR) wild-type and transgenic cytotoxic (CD8 C ) T cells against ES. Patients and Methods: Three refractory HLA-A2 C ES patients were treated with HLA-A Ã 02:01/peptidespecific allorepertoire-derived (i.e., allorestricted) CD8 C T cells. Patient #1 received up to 4.8 £ 10 5 /kg body weight HLA-A Ã 02:01 ¡ allorestricted donor-derived wild-type CD8 C T cells. Patient #2 received up to 8.2 £ 10 6 /kg HLA-A Ã 02:01 ¡ donor-derived and patient #3 up to 6 £ 10 6 /kg autologous allorestricted TCR transgenic CD8 C T cells. All patients were treated with the same TCR complementary determining region 3 allorecognition sequence for CHM1 peptide 319 (CHM1 319 ). Results: HLA-A Ã 02:01/CHM1 319 -specific allorestricted CD8 C T cells showed specific in vitro lysis of all patient-derived ES cell lines. Therapy was well tolerated and did not cause graft versus host disease (GvHD). Patients #1 and #3 showed slow progression, whereas patient #2, while having BM involvement, showed partial metastatic regression associated with T cell homing to involved lesions. CHM1 319 TCR transgenic T cells could be tracked in his BM for weeks. Conclusions: CHM1 319 -TCR transgenic T cells home to affected BM and may cause partial disease regression. HLA-A Ã 02:01/antigen-specific allorestricted T cells proliferate in vivo without causing GvHD.

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Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy

Abstract: Key Points CD19-targeted CAR-T-cell therapy of patients with MLL-rearranged B-ALL effectively induced marrow remission of B-ALL. Patients with MLL-rearranged B-ALL who attain CR after CD19 CAR-T-cell therapy may be at risk for relapse with clonally related AML.

Cited by 624 publications

References 14 publications

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

Sequential loss of tumor surface antigens following chimeric antigen receptor T-cell therapies in diffuse large B-cell lymphoma

The full transforming capacity of MLL-Af4 is interlinked with lymphoid lineage commitment

Ewing sarcoma partial regression without GvHD by chondromodulin-I/HLA-A*02:01-specific allorestricted T cell receptor transgenic T cells

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