Antibody therapy of non-Hodgkin's B-cell lymphoma

Diffuse large cell B cell lymphoma (DLBCL) accounts for approximately 30%–40% of all non-Hodgkin lymphoma (NHL) cases. Current first line DLBCL treatment results in long-term remission in more than 60% of cases. However, those patients with primary refractory disease or early relapse exhibit poor prognosis, highlighting a requirement for alternative therapies. Our aim was to develop a novel model of DLBCL that facilitates in vitro testing of current and novel therapies by replicating key components of the tumor microenvironment (TME) in a three-dimensional (3D) culture system that would enable primary DLBCL cell survival and study ex vivo. The TME is a complex ecosystem, comprising malignant and non-malignant cells, including cancer-associated fibroblasts (CAF) and tumor-associated macrophages (TAM) whose reciprocal crosstalk drives tumor initiation and growth while fostering an immunosuppressive milieu enabling its persistence. The requirement to recapitulate, at least to some degree, this complex, interactive network is exemplified by the rapid cell death of primary DLBCL cells removed from their TME and cultured alone in vitro. Building on previously described methodologies to generate lymphoid-like fibroblasts from adipocyte derived stem cells (ADSC), we confirmed lymphocytes, specifically B cells, interacted with this ADSC-derived stroma, in the presence or absence of monocyte-derived macrophages (MDM), in both two-dimensional (2D) cultures and a 3D collagen-based spheroid system. Furthermore, we demonstrated that DLBCL cells cultured in this system interact with its constituent components, resulting in their improved viability as compared to ex-vivo 2D monocultures. We then assessed the utility of this system as a platform to study therapeutics in the context of antibody-directed phagocytosis, using rituximab as a model immunotherapeutic antibody. Overall, we describe a novel 3D spheroid co-culture system comprising key components of the DLBCL TME with the potential to serve as a testbed for novel therapeutics, targeting key cellular constituents of the TME, such as CAF and/or TAM.

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Macrophage-Mediated Antibody Dependent Effector Function in Aggressive B-Cell Lymphoma Treatment is Enhanced by Ibrutinib via Inhibition of JAK2

Cancers ◽

10.3390/cancers12082303 ◽

2020 ◽

Vol 12 (8) ◽

pp. 2303

Author(s):

Verena Barbarino ◽

Sinika Henschke ◽

Stuart Blakemore ◽

Elena Izquierdo ◽

Michael Michalik ◽

...

Keyword(s):

Monoclonal Antibody ◽

B Cell ◽

Cell Lymphoma ◽

Antibody Therapy ◽

B Cell Lymphoma ◽

Lymphocytic Leukemia ◽

Janus Kinase ◽

Monoclonal Antibody Therapy ◽

Antibody Treatment ◽

Btk Inhibitors

Targeted inhibition of Bruton’s Tyrosine Kinase (BTK) with ibrutinib and other agents has become important treatment options in chronic lymphocytic leukemia, Waldenström’s Macroglobulinemia, Mantle cell lymphoma, and non-GCB DLBCL. Clinical trials combining small molecule inhibitors with monoclonal antibodies have been initiated at rapid pace, with the biological understanding between their synergistic interactions lagging behind. Here, we have evaluated the synergy between BTK inhibitors and monoclonal antibody therapy via macrophage mediated antibody dependent cellular phagocytosis (ADCP). Initially, we observed increased ADCP with ibrutinib, whilst second generation BTK inhibitors failed to synergistically interact with monoclonal antibody treatment. Kinase activity profiling under BTK inhibition identified significant loss of Janus Kinase 2 (JAK2) only under ibrutinib treatment. We validated this potential off-target effect via JAK inhibition in vitro as well as with CRISPR/Cas9 JAK2−/− experiments in vivo, showing increased ADCP and prolonged survival, respectively. This data supports inhibition of the JAK-STAT (Signal Transducers and Activators of Transcription) signaling pathway in B-cell malignancies in combination with monoclonal antibody therapy to increase macrophage-mediated immune responses.

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Combination Antibody Therapy With Epratuzumab and Rituximab in Relapsed or Refractory Non-Hodgkin's Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2005.13.821 ◽

2005 ◽

Vol 23 (22) ◽

pp. 5044-5051 ◽

Cited By ~ 130

Author(s):

John P. Leonard ◽

Morton Coleman ◽

Jamie Ketas ◽

Michelle Ashe ◽

Jennifer M. Fiore ◽

...

Keyword(s):

High Risk ◽

Follicular Lymphoma ◽

B Cell ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Antibody Therapy ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Hodgkin's Lymphoma ◽

Non Hodgkin's Lymphoma

Purpose To explore the safety and therapeutic activity of combination anti–B-cell monoclonal antibody therapy in non-Hodgkin's lymphoma (NHL). Patients and Methods Twenty-three patients with recurrent B-cell lymphoma received anti-CD22 epratuzumab 360 mg/m2 and anti-CD20 rituximab 375 mg/m2 monoclonal antibodies weekly for four doses each. Sixteen patients had indolent histologies (15 with follicular lymphoma) and seven had aggressive NHL (all diffuse large B-cell lymphoma [DLBCL]). Indolent patients had received a median of one (range, one to six) prior treatment, with 31% refractory to their last therapy and 81% with high-risk Follicular Lymphoma International Prognostic Index scores. Patients with DLBCL had a median of three (range, one to eight) prior regimens (14% resistant to last treatment) and 71% had high intermediate–risk or high-risk International Prognostic Index scores. All patients were rituximab naïve. Results Treatment was well tolerated, with toxicities principally infusion-related and predominantly grade 1 or 2. Ten (67%) patients with follicular NHL achieved an objective response (OR), including nine of 15 (60%) with complete responses (CRs and unconfirmed CRs). Four of six assessable patients (67%) with DLBCL achieved an OR, including three (50%) CRs. Median time to progression for all indolent NHL patients was 17.8 months. Conclusion The full-dose combination of epratuzumab with rituximab was well tolerated and had significant clinical activity in NHL, suggesting that this combination should be tested in comparison with single-agent treatment.

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Anti-CD20 monoclonal antibody therapy in Epstein-Barr virus–associated B cell lymphoma following lung transplantation

The Journal of Heart and Lung Transplantation ◽

10.1016/s1053-2498(00)00087-5 ◽

2000 ◽

Vol 19 (5) ◽

pp. 492-495 ◽

Cited By ~ 14

Author(s):

Martine Reynaud-Gaubert ◽

Anne Marie Stoppa ◽

Jean-Yves Gaubert ◽

Pascal Thomas ◽

Pierre Fuentes

Keyword(s):

Monoclonal Antibody ◽

B Cell ◽

Epstein Barr Virus ◽

Cell Lymphoma ◽

Antibody Therapy ◽

B Cell Lymphoma ◽

Monoclonal Antibody Therapy ◽

Barr Virus ◽

Epstein Barr ◽

Anti Cd20

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Standard International Prognostic Index Remains a Valid Predictor of Outcome for Patients With Aggressive CD20+B-Cell Lymphoma in the Rituximab Era

Journal of Clinical Oncology ◽

10.1200/jco.2009.26.2493 ◽

2010 ◽

Vol 28 (14) ◽

pp. 2373-2380 ◽

Cited By ~ 333

Author(s):

Marita Ziepert ◽

Dirk Hasenclever ◽

Evelyn Kuhnt ◽

Bertram Glass ◽

Norbert Schmitz ◽

...

Keyword(s):

Risk Stratification ◽

B Cell ◽

Proportional Hazards ◽

Cell Lymphoma ◽

International Prognostic Index ◽

Antibody Therapy ◽

Prognostic Index ◽

B Cell Lymphoma ◽

Significant Prognostic Factor ◽

End Points

PurposeThe International Prognostic Index (IPI) is widely used for risk stratification of patients with aggressive B-cell lymphoma. The introduction of rituximab has markedly improved outcome, and R-CHOP (rituximab + cyclophosphamide, doxorubicin, vincristine, prednisone) has become the standard treatment for CD20+diffuse large B-cell lymphoma. To investigate whether the IPI has maintained its power for risk stratification when rituximab is combined with CHOP, we analyzed the prognostic relevance of IPI in three prospective clinical trials.Patients and MethodsIn total, 1,062 patients treated with rituximab were included (MabThera International Trial [MInT], 380 patients; dose-escalated regimen of cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone (MegaCHOEP) trial, 72 patients; CHOP + rituximab for patients older than age 60 years [RICOVER-60] trial, 610 patients). A multivariate proportional hazards modeling was performed for single IPI factors under rituximab on event-free, progression-free, and overall survival.ResultsIPI score was significant for all three end points. Rituximab significantly improved treatment outcome within each IPI group resulting in a quenching of the Kaplan-Meier estimators. However, IPI was a significant prognostic factor in all three end points and the ordering of the IPI groups remained valid. The relative risk estimates of single IPI factors and their order in patients treated with R-CHOP were similar to those found with CHOP.ConclusionThe effects of rituximab were superimposed on the effects of CHOP with no interactions between chemotherapy and antibody therapy. These results demonstrate that the IPI is still valid in the R-CHOP era.

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