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A Novel Therapy for Lymphoma Using T-Cell Bispecific Antibodies Ajay Prakash1 and Catherine S

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A Novel Therapy for Lymphoma Using T-Cell Bispecific Antibodies Ajay Prakash1 and Catherine S Author Manuscript Published OnlineFirst on June 8, 2018; DOI: 10.1158/1078-0432.CCR-18-1363 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Immunity War: A Novel Therapy for Lymphoma Using T-cell Bispecific Antibodies Ajay Prakash1 and Catherine S. Diefenbach1 1. NYU Perlmutter Cancer Center, Department of Hematology-Oncology Corresponding Author: Catherine Diefenbach; NYU Perlmutter Cancer Center; 240 East 38th Street, 19th Floor, NY NY 10016; 212 731-5670; email: [email protected] Disclosures: CD: Research funding, Consulting Genentech Running title: A Novel Lymphoma Therapy Using T-cell Bispecific Antibodies Summary The activity of T cell mediated immunotherapies in B cell lymphoma has been limited to date. The novel bispecific antibody CD20-TCB, has a 2:1 antibody design to maximize T cell engagement, and demonstrates activity in preclinical models. This may represent a novel therapeutic approach for patients with relapsed/refractory NHL. Main Text In this issue of Clinical Cancer Research, Bacac and colleagues investigate the pre-clinical efficacy of a bispecific antibody in the treatment of lymphoma (1). To date, immunotherapy for the treatment of non-Hodgkin lymphoma (NHL) has been primarily focused on monoclonal antibody therapy, which has demonstrated both single agent activity and substantial synergy with cytotoxic chemotherapy (2). Further development of immunotherapy has been mixed. Chimeric antigen (CAR) T-cell therapy has demonstrated exciting activity with significant potential toxicities, and some preliminary successes have been seen with antibody drug conjugates. However, checkpoint blockade and other novel approaches have been complicated by disappointing activity as well as off-target side effects. In this report on the novel bispecific antibody CD20-TCB, the authors demonstrate an asymmetric design, and B-cell depletion pre- treatment which may decrease off target effects, improve the safety profile, and potentially the 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 8, 2018; DOI: 10.1158/1078-0432.CCR-18-1363 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. response rate. This molecule represents a new approach for the treatment of relapsed and refractory NHL. Therapeutic antibody design in B-cell malignancies has benefited greatly from our current understanding of rituximab’s mechanism of action (2). This anti-CD20 monoclonal antibody appears to have a multitude of downstream effects, including cell-independent apoptosis, complement mediated cytotoxicity, and antibody dependent cytotoxicity. While similar anti-CD20 molecules obinutuzumab and ofatumumab have shown efficacy in the treatment of various B- cell malignancies (Figure 1), the absence of a single identifiable signaling pathway complicates the development of further therapeutic small molecules and antibodies. Blinatumomab, a bispecific antibody consisting of a pair of anti-CD19 and anti-CD3 antibody fragments with a small-molecule linker, showed promise in pre-clinical models, and in acute lymphocytic leukemia (ALL), but has not demonstrated significant activity in NHL (2). In this report, Bacac and colleagues propose an interesting modification to prior antibody design. Their primary protein contains a head-to-tail configuration of anti-CD20 to anti-CD3 antibodies, similar to that seen in blinatumomab. To this design, they add yet another anti-CD20 antibody across the hinge region, connected by a modified Fc chain, resulting in the novel antibody, CD20-TCB. The authors then use the preclinical surrogates of B-cell depletion and cell lysis to compare CD20- TCB with a single-armed bispecific antibody and another control antibody with a single anti-CD3 and anti-CD20 antibody on each Fab arm. Using in vitro cytotoxicity assays, the authors determine that their CD20-TCB molecule is, on average, 40 fold more potent than the other 1:1 conformations across multiple malignant B-cell lines (1). The choice of these controls is important as it demonstrates that both the head-to-tail conformation anti-CD20/anti-CD3 molecule and the duplicate anti-CD20 moiety on the opposing Fab arm are critical to the potency of this novel antibody. These data are intriguing, yet it is important to note that potency and toxicity are often correlative. While cytokine levels are evaluated as a surrogate for toxicity, the clinical picture is far more complicated than this. The relative toxicity of CD20-TCB compared to existing NHL therapies requires further study. The authors’ modifications to the Fc chain of their antibody present an interesting aside. As noted above, rituximab takes advantage of a number of non-specific immunomodulatory effects to perform its anti-tumor effect (3). It is known, for example, that the IgG Fc domain activates 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 8, 2018; DOI: 10.1158/1078-0432.CCR-18-1363 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. cytotoxic activity thorough the Fc-γ receptor (FcγR) on a number of immune cells including NK cells, macrophages, and neutrophils. In addition, this region is known to activate complement through C1q and the complement cascade. Bacac and colleagues have abrogated both of these effects through modifications in the Fc domain, which further emphasizes that their molecule’s mechanism of action is primarily through the recruitment of T-cells. This is confirmed by their in vitro culture assay demonstrating that tumor lysis is dependent on T-cell recruitment and activation, with a preferential activation/expansion of CD8 cell populations. The dosing, efficacy and toxicity of CD20-TCB needs to be further evaluated in phase I clinical trials in order to better understand the consequences of the authors’ design on clinical management. The cytokine release syndrome (CRS) associated with activation and release of inflammatory cytokines in the setting of supraphysiologic immune stimulation, is a potential side effect of this and other bispecific antibodies, as well as chimeric antigen T-cells (4). The CRS reaction typically occurs within minutes to hours after infusion initiation, with the incidence of the symptoms typically corresponding to the overall lymphocyte/malignancy burden. Symptoms may vary from fever and organ toxicity, to cardiovascular dysfunction and organ failure, and are primarily driven through the pro-inflammatory actions of IL-6 (5). Classically, this has been managed through dose escalation or step-up-dosing (SUD), with treatment of severe symptoms incorporating corticosteroids or the anti-IL6R antibody tocilizumab. Here, the authors propose using obinutuzumab, a type-II monoclonal CD-20 antibody, to deplete B-cells and reduce cytokine release in response to CD20-TCB infusion. While the mechanism is sound, and there is demonstrable decrease in cytokine peak following this method in comparison to SUD, verification in phase I studies will be critical. This is because, as noted, obinutuzumab is itself an anti-CD20 antibody with well documented infusion reactions (5). The authors have somewhat anticipated this critique with an in vivo analysis of pro-inflammatory cytokine levels in their animal models. However, there are no data showing a clear relationship between cytokine levels and symptom severity in individual patients, especially given that malignancy is itself a pro-inflammatory state. Thus, while this pre-clinical data is promising regarding treatment- related toxicity, further clinical validation is necessary before safety of this approach can be confirmed. 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research. Author Manuscript Published OnlineFirst on June 8, 2018; DOI: 10.1158/1078-0432.CCR-18-1363 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. The data presented by Bacac and colleagues represents an exciting step forward in the treatment of NHL. By demonstrating preclinically the superior potency of asymmetric bispecific antibody design, theses data argue for the evaluation of asymmetric antibodies for current bispecific targets, especially those that use CD3-driven T-cell recruitment as their primary mechanism of action. Given the proven efficacy of blinatumomab in B-cell ALL, it would be interesting to recapitulate the authors’ design with a 2:1 anti-CD19/anti-CD3 bispecific antibody and evaluate its efficacy in B-cell malignancies. Another future direction may be to evaluate whether a mirrored antibody design with head-to-tail linkers on both Fab regions may lead to an even greater increase in in vitro efficacy, and the relative toxicity of that approach. These and other approaches could then be replicated across our known catalogue of cell surface targets expanding our pool of potential therapeutics significantly. The CD20-TCB designed by Bacac and colleagues, offers both exciting preclinical activity and new avenues for antibody development in NHL. For patients with relapsed and refractory NHL these developments cannot come soon enough. 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2018 American Association for Cancer Research.
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