Emerging Therapies for the Treatment of Relapsed or Refractory Follicular Lymphoma

MacDonald, David; Prica, Anca; Assouline, Sarit; Christofides, Anna; Lawrence, T.; Sehn, Laurie H.

doi:10.3747/co.23.3405

Cited by 10 publications

(4 citation statements)

References 34 publications

(65 reference statements)

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“…However, a large number of patients become refractory to rituximab with time thus representing a growing population with an unmet medical need (4). Several emerging therapies for the treatment of relapsed or refractory B cell lymphomas are in development (47), including the biAb approach presented here. A plethora of ongoing trials are evaluating the efficacy of rituximab combined with checkpoint inhibitors and other immune therapies for lymphoma (48).…”

Section: Discussionmentioning

confidence: 99%

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Buatois

Johnson

Salgado-Pires

et al. 2018

Molecular Cancer Therapeutics

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CD47, an ubiquitously expressed innate immune checkpoint receptor that serves as a universal "don't eat me" signal of phagocytosis, is often upregulated by hematologic and solid cancers to evade immune surveillance. Development of CD47-targeted modalities is hindered by the ubiquitous expression of the target, often leading to rapid drug elimination and hemotoxicity including anemia. To overcome such liabilities, we have developed a fully human bispecific antibody, NI-1701, designed to coengage CD47 and CD19 selectively on B cells. NI-1701 demonstrates favorable elimination kinetics with no deleterious effects seen on hematologic parameters following single or multiple administrations to nonhuman primates. Potent and activity is induced by NI-1701 to kill cancer cells across a plethora of B-cell malignancies and control tumor growth in xenograft mouse models. The mechanism affording maximal tumor growth inhibition by NI-1701 is dependent on the coengagement of CD47/CD19 on B cells inducing potent antibody-dependent cellular phagocytosis of the targeted cells. NI-1701-induced control of tumor growth in immunodeficient NOD/SCID mice was more effective than that achieved with the anti-CD20 targeted antibody, rituximab. Interestingly, a synergistic effect was seen when tumor-implanted mice were coadministered NI-1701 and rituximab leading to significantly improved tumor growth inhibition and regression in some animals. We describe herein, a novel bispecific antibody approach aimed at sensitizing B cells to become more readily phagocytosed and eliminated thus offering an alternative or adjunct therapeutic option to patients with B-cell malignancies refractory/resistant to anti-CD20-targeted therapy. .

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Section: Discussionmentioning

confidence: 99%

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Buatois

Johnson

Salgado-Pires

et al. 2018

Molecular Cancer Therapeutics

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“…In light of the ubiquitous application of rituximab in frontline treatment regimens, the emergence of rituximab-resistant disease is a problem [83]. The GADOLIN trial tested the efficacy and safety of obinutuzumab plus bendamustine against bendamustine alone in 413 patients who had rituximab-refractory indolent NHL [84].…”

Section: Treatment Of Relapsed/refractory Follicular Lymphomamentioning

confidence: 99%

Diagnosis and treatment of follicular lymphoma: an update

et al. 2018

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Over the last few years, there have been many changes in the management of patients with follicular lymphoma, resulting in improvements in progression-free survival and quality of life. In addition to established regimens such as radiotherapy and immunochemotherapy, new treatment options are on the horizon. Furthermore, even the use of established chemotherapy agents has evolved, with new combinations moving to the forefront of the current treatment strategy. Nevertheless, there remains an unmet need for patients who have early relapses, those who are not responsive to anti-CD20 treatment regimens and for those in whom minimal residual disease persists even after immunochemotherapy. This review provides a summary of current developments in the diagnosis, treatment and management of follicular lymphoma, focusing on the clinical issues from a Swiss perspective.

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“…Indeed, both DC-SIGN-mediated BCR signaling and cross talk of M2 macrophages with FL cells were inhibited in vitro by BTK and SYK inhibitors ( 14 , 15 ), revealing their therapeutic potential. Ongoing clinical trials are currently analyzing the therapeutic efficacy of signal transduction inhibitors in FL patients and in other B-cell malignancies that depend on BCR signaling ( 46 – 48 ).…”

Section: Therapeutic Targeting Of Altered Glycansmentioning

confidence: 99%

Altered N-Linked Glycosylation in Follicular Lymphoma and Chronic Lymphocytic Leukemia: Involvement in Pathogenesis and Potential Therapeutic Targeting

Hollander

Haimovich

2017

Front. Immunol.

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B-cell antigen receptor (BCR) expression is indispensable for survival of most B-cell malignancies. In follicular lymphoma (FL), N-linked glycosylation sites are introduced in the immunoglobulin (Ig) variable region genes. Oligosaccharides added to the acquired sites are unusually of the high-mannose type. These glycans interact with mannose-specific lectins, especially with dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin (DC-SIGN). Lectin binding to FL triggers persistent activating signals, suggesting that lectins within the tumor microenvironment promote cell survival and proliferation. Insertion of N-glycosylation sites in Ig variable region genes has been detected in other germinal center-associated lymphomas, specifically in subsets of diffuse large B-cell lymphomas and Burkitt’s lymphomas, suggesting involvement of altered glycans in pathogenesis of these malignancies as well. Furthermore, the BCR in chronic lymphocytic leukemia (CLL) carries high-mannose oligosaccharides, albeit in the heavy chain constant rather than variable region. The high expression level of the unique glycoform, particularly in the more aggressive unmutated CLL subset, suggests a functional significance for this glycan in CLL. As lectin interaction with the BCR is critical for FL and probably for some other lymphomas, targeting this interaction is considered to be an interesting therapeutic strategy. Reagents for blockade of lectin–BCR interaction may include antibodies against high-mannose glycans and mannose-based oligosaccharide mimics or non-carbohydrate glycomimetics. Moreover, as this interaction triggers signaling pathways similar to those demonstrated for BCR engagement by antigen, BCR signal transduction inhibitors may emerge as effective therapeutics for lectin-driven malignancies.

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Emerging Therapies for the Treatment of Relapsed or Refractory Follicular Lymphoma

Cited by 10 publications

References 34 publications

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Preclinical Development of a Bispecific Antibody that Safely and Effectively Targets CD19 and CD47 for the Treatment of B-Cell Lymphoma and Leukemia

Diagnosis and treatment of follicular lymphoma: an update

Altered N-Linked Glycosylation in Follicular Lymphoma and Chronic Lymphocytic Leukemia: Involvement in Pathogenesis and Potential Therapeutic Targeting

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