Targeting the B-cell receptor pathway: a review of current and future therapies for non-Hodgkin’s lymphoma

Abstract Non-Hodgkin’s lymphoma (NHL) is an attractive indication for the use of antibody-drug conjugate (ADC) therapeutics since NHL is responsive to conventional chemotherapeutic and antibody treatments. Additionally, experience with rituximab indicates that depletion of normal B-cells can be tolerated without untoward side effects, suggesting that B-cell specific surface proteins that are also prevalent in NHL are potential ADC targets. ADCs with stable linkers have lower toxicity than ADCs containing the same drugs with less stable linkers, however, for these ADCs to be effective the antibody must be degraded to release the active drug. This limits potential targets to surface antigens that upon antibody binding are highly internalized and subsequently degraded. We hypothesized that components of the B-cell receptor (BCR) would be excellent targets for stable-linker ADCs since, when cross-linked, the BCR is targeted to the lysosomal-like compartment MIIC as part of B-cell antigen presentation. In particular, CD79, the signaling component of the B-cell receptor, comprised of two peptide chains CD79a (Igα, mb-1) and CD79b (Igβ, B29), seemed a promising target for ADC treatment of NHL. CD79’s expression is restricted to the B-cell lineage and is on the surface of almost all NHLs. Unlike surface-Ig targeted therapies, which require a new drug for each cancer clone, CD79 sequences are invariant and a single drug is appropriate for the entire population. We found that ADCs targeted to CD79b were more effective than those targeted to CD79a. Furthermore, excellent efficacy is demonstrated with ADCs containing stable linkers and our data indicate in particular, that both anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are effective at low doses in subcutaneous cell-line xenograft models of follicular lymphoma, mantle cell lymphoma, Burkitt’s lymphoma and disseminated Burkitt’s lymphoma. Mechanism-of-action experiments show that anti-CD79b antibodies down regulate surface BCR expression and internalized antibody accumulates in the lysosomal-like MIIC compartment as hypothesized. We evaluated a number of ADCs targeted to other B-cell antigens and found that they were not effective if the ADC had a stable linker, indicating that CD79 has special properties as a target for ADCs. Our results suggest that anti-CD79b-MCC-DM1 and anti-CD79b-MC-MMAF are particularly promising therapeutics for the treatment of NHL.

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Faculty Opinions recommendation of Rituximab for High-Risk, Mature B-Cell Non-Hodgkin's Lymphoma in Children.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.738071477.793575433 ◽

2020 ◽

Author(s):

Martine van Grotel

Keyword(s):

High Risk ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Hodgkin's Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

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Use of pembrolizumab with or without pomalidomide in HIV-associated non-Hodgkin’s lymphoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-002097 ◽

2021 ◽

Vol 9 (2) ◽

pp. e002097

Author(s):

Kathryn Lurain ◽

Ramya Ramaswami ◽

Ralph Mangusan ◽

Anaida Widell ◽

Irene Ekwede ◽

...

Keyword(s):

B Cell ◽

Hodgkin’S Lymphoma ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Hiv And Aids ◽

Hodgkin's Lymphoma ◽

People Living With Hiv ◽

Oncogenic Viruses ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

BackgroundNon-Hodgkin’s lymphoma (NHL) is currently the most common malignancy among people living with HIV (PLWH) in the USA. NHL in PLWH is more frequently associated with oncogenic viruses than NHL in immunocompetent individuals and is generally associated with increased PD-1 expression and T cell exhaustion. An effective immune-based second-line approach that is less immunosuppressive than chemotherapy may decrease infection risk, improve immune control of oncogenic viruses, and ultimately allow for better lymphoma control.MethodsWe conducted a retrospective study of patients with HIV-associated lymphomas treated with pembrolizumab±pomalidomide in the HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute.ResultsWe identified 10 patients with stage IV relapsed and/or primary refractory HIV-associated NHL who were treated with pembrolizumab, an immune checkpoint inihibitor, with or without pomalidomide. Five patients had primary effusion lymphoma (PEL): one had germinal center B cell-like (GCB) diffuse large B cell lymphoma (DLBCL); two had non-GCB DLBCL; one had aggressive B cell lymphoma, not otherwise specified; and one had plasmablastic lymphoma. Six patients received pembrolizumab alone at 200 mg intravenously every 3 weeks, three received pembrolizumab 200 mg intravenously every 4 weeks plus pomalidomide 4 mg orally every day for days 1–21 of a 28-day cycle; and one sequentially received pembrolizumab alone and then pomalidomide alone. The response rate was 50% with particular benefit in gammaherpesvirus-associated tumors. The progression-free survival was 4.1 months (95% CI: 1.3 to 12.4) and overall survival was 14.7 months (95% CI: 2.96 to not reached). Three patients with PEL had leptomeningeal disease: one had a complete response and the other two had long-term disease control. There were four immune-related adverse events (irAEs), all CTCAEv5 grade 2–3; three of the four patients were able to continue receiving pembrolizumab. No irAEs occurred in patients receiving the combination of pembrolizumab and pomalidomide.ConclusionsTreatment of HIV-associated NHL with pembrolizumab with or without pomalidomide elicited responses in several subtypes of HIV-associated NHL. This approach is worth further study in PLWH and NHL.

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Prognostic significance of bcl-2 protein expression in aggressive non- Hodgkin's lymphoma. Groupe d'Etude des Lymphomes de l'Adulte (GELA)

Blood ◽

10.1182/blood.v87.1.265.265 ◽

1996 ◽

Vol 87 (1) ◽

pp. 265-272 ◽

Cited By ~ 332

Author(s):

O Hermine ◽

C Haioun ◽

E Lepage ◽

MF d'Agay ◽

J Briere ◽

...

Keyword(s):

Overall Survival ◽

Protein Expression ◽

B Cell ◽

Hodgkin’S Lymphoma ◽

Prognostic Significance ◽

Hodgkin's Lymphoma ◽

Independent Effect ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma ◽

Large B Cell

Abstract Little is known about the expression of bcl-2 protein in intermediate and high grade non-Hodgkin's lymphoma (NHL) and its clinical and prognostic significance. We performed immunohistochemical analysis of bcl-2 expression in tumoral tissue sections of 348 patients with high or intermediate grade NHL. These patients were uniformly treated with adriamycin, cyclophosphamide, vindesine, bleomycin, and prednisone (ACVBP) in the induction phase of the LNH87 protocol. Fifty eight cases were excluded due to inadequate staining. Of the 290 remaining patients, 131 (45%) disclosed homogeneous positivity (high bcl-2 expression) in virtually all tumor cells, whereas 65 (23%) were negative and 94 (32%) exhibited intermediate staining. High bcl-2 expression was more frequent in B-cell NHL (109 of 214, 51%) than in T- cell NHL (6 of 35, 17%) (P = .0004), and was heterogeneously distributed among the different histological subtypes. Further analysis was performed on the 151 patients with diffuse large B-cell lymphoma (centroblastic and immunoblastic) to assess the clinical significance and potential prognostic value of bcl-2 expression in the most frequent and homogeneous immunohistological subgroup. High bcl-2 expression, found in 44% of these patients (67 of 151), was more frequently associated with III-IV stage disease (P = .002). Reduced disease-free survival (DFS) (P < .01) and overall survival (P < .05) were demonstrated in the patients with high bcl-2 expression. Indeed, the 3-year estimates of DFS and overall survival were 60% and 61%, respectively (high bcl-2 expression) versus 82% and 78%, respectively (negative/intermediate bcl-2 expression). A multivariate regression analysis confirmed the independent effect of bcl-2 protein expression on DFS. Thus bcl-2 protein expression, as demonstrated in routinely paraffin-embedded tissue, appears to be predictive of poor DFS, in agreement with the role of bcl-2 in chemotherapy-induced apoptosis. It might be considered as a new independent biologic prognostic parameter, which, especially in diffuse large B-cell NHL, could aid in the identification of patient risk groups.

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429 Induction of interleukin-6 by HCV core protein in patients with HCV-associated cryoglobulinemia and B-cell non-Hodgkin's lymphoma

Journal of Hepatology ◽

10.1016/s0168-8278(05)81841-0 ◽

2005 ◽

Vol 42 ◽

pp. 157

Keyword(s):

B Cell ◽

Interleukin 6 ◽

Hodgkin’S Lymphoma ◽

Core Protein ◽

Hodgkin's Lymphoma ◽

Non Hodgkin’S Lymphoma ◽

Hcv Core Protein ◽

Non Hodgkin's Lymphoma

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Review of the Safety and Feasibility of Rapid Infusion of Rituximab

Journal of Oncology Practice ◽

10.1200/jop.200001 ◽

2010 ◽

Vol 6 (2) ◽

pp. 91-93 ◽

Cited By ~ 19

Author(s):

Jill Atmar

Keyword(s):

B Cell ◽

Hodgkin’S Lymphoma ◽

Lymphocytic Leukemia ◽

Hodgkin's Lymphoma ◽

Standard Chemotherapy ◽

Rapid Infusion ◽

Non Hodgkin’S Lymphoma ◽

Non Hodgkin's Lymphoma

Added to standard chemotherapy, rituximab improved survival in patients with non-Hodgkin's lymphoma; added to fludarabine-based regimens, it improved response and survival in patients with chronic B-cell lymphocytic leukemia.

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