Chimeric antigen receptor T-cell therapy in relapsed or refractory mantle cell lymphoma: a systematic review and meta-analysis.

Background: Chimeric antigen receptor (CAR) T-cell therapy (CAR-T therapy) has demonstrated significant efficacy in the ZUMA-2 study. After regulatory approvals, several clinical trials and real-world studies on CAR-T therapy for relapsed or refractory mantle cell lymphoma (R/R MCL) were conducted. However, data on clinical safety and efficacy are inconsistent. In this study, we aimed to conduct a systematic analysis of the effectiveness and safety of CAR-T therapy across a wider and more representative cohort of patients with R/R MCL. Methods: We performed a systematic review and meta-analysis of studies on patients with R/R MCL who received CAR-T cell therapy. Data were extracted and consolidated, with primary focus on the evaluation of safety and efficacy outcome measures. This study has not been registered with PROSPERO. Results: This meta-analysis identified and included 16 studies with 984 patients. The pooled estimate for overall response rate (ORR) was 89%; complete remission (CR) rate was 74%. The 6-month and 12-month progression-free survival (PFS) rates were 69% and 53%, respectively, while the overall survival (OS) rates were 80% and 69%, respectively. Cytokine release syndrome (CRS) of grade 3 or higher was observed in 8% of patients, whereas neurotoxicity of grade 3 or higher was observed in 22% of patients. The risk of bias was assessed as low in 9 studies and moderate in 7 studies. Conclusion: CAR-T therapy exhibited promising efficacy and manageable adverse reactions in patients with R/R MCL.

CD163+ macrophages in mantle cell lymphoma induce activation of prosurvival pathways and immune suppression.

ABSTRACT: Mantle cell lymphoma (MCL) is dependent on a supportive tumor immune microenvironment (TIME) in which infiltration of CD163+ macrophages has a negative prognostic impact. This study explores how abundance and spatial localization of CD163+ cells are associated with the biology of MCL, using spatial multiomic investigations of tumor and infiltrating CD163+ and CD3+ cells. A total of 63 proteins were measured using GeoMx digital spatial profiling in tissue microarrays from 100 diagnostic MCL tissues. Regions of interest were selected in tumor-rich and tumor-sparse tissue regions. Molecular profiling of CD163+ macrophages, CD20+ MCL cells, and CD3+ T-cells was performed. To validate protein profiles, 1811 messenger RNAs were measured in CD20+ cells and 2 subsets of T cells. Image analysis was used to extract the phenotype and position of each targeted cell, thereby allowing the exploration of cell frequencies and cellular neighborhoods. Proteomic investigations revealed that CD163+ cells modulate their immune profile depending on their localization and that the immune inhibitory molecules, V-domain immunoglobulin suppressor of T-cell activation and B7 homolog 3, have higher expression in tumor-sparse than in tumor-rich tissue regions and that targeting should be explored. We showed that MCL tissues with more abundant infiltration of CD163+ cells have a higher proteomic and transcriptional expression of key components of the MAPK pathway. Thus, the MAPK pathway may be a feasible therapeutic target in patients with MCL with CD163+ cell infiltration. We further showed the independent and combined prognostic values of CD11c and CD163 beyond established risk factors.

CAR19 monitoring by peripheral blood immunophenotyping reveals histology-specific expansion and toxicity.

ABSTRACT: Chimeric antigen receptor (CAR) T cells directed against CD19 (CAR19) are a revolutionary treatment for B-cell lymphomas (BCLs). CAR19 cell expansion is necessary for CAR19 function but is also associated with toxicity. To define the impact of CAR19 expansion on patient outcomes, we prospectively followed a cohort of 236 patients treated with CAR19 (brexucabtagene autoleucel or axicabtagene ciloleucel) for mantle cell lymphoma (MCL), follicular lymphoma, and large BCL (LBCL) over the course of 5 years and obtained CAR19 expansion data using peripheral blood immunophenotyping for 188 of these patients. CAR19 expansion was higher in patients with MCL than other lymphoma histologic subtypes. Notably, patients with MCL had increased toxicity and required fourfold higher cumulative steroid doses than patients with LBCL. CAR19 expansion was associated with the development of cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and the requirement for granulocyte colony-stimulating factor 14 days after infusion. Younger patients and those with elevated lactate dehydrogenase (LDH) had significantly higher CAR19 expansion. In general, no association between CAR19 expansion and LBCL treatment response was observed. However, when controlling for tumor burden, we found that lower CAR19 expansion in conjunction with low LDH was associated with improved outcomes in LBCL. In sum, this study finds CAR19 expansion principally associates with CAR-related toxicity. Additionally, CAR19 expansion as measured by peripheral blood immunophenotyping may be dispensable to favorable outcomes in LBCL.

A BAFF ligand-based CAR-T cell targeting three receptors and multiple B cell cancers.

B cell-activating factor (BAFF) binds the three receptors BAFF-R, BCMA, and TACI, predominantly expressed on mature B cells. Almost all B cell cancers are reported to express at least one of these receptors. Here we develop a BAFF ligand-based chimeric antigen receptor (CAR) and generate BAFF CAR-T cells using a non-viral gene delivery method. We show that BAFF CAR-T cells bind specifically to each of the three BAFF receptors and are effective at killing multiple B cell cancers, including mantle cell lymphoma (MCL), multiple myeloma (MM), and acute lymphoblastic leukemia (ALL), in vitro and in vivo using different xenograft models. Co-culture of BAFF CAR-T cells with these tumor cells results in induction of activation marker CD69, degranulation marker CD107a, and multiple proinflammatory cytokines. In summary, we report a ligand-based BAFF CAR-T capable of binding three different receptors, minimizing the potential for antigen escape in the treatment of B cell cancers.

Chemical Synthesis of Antibody-Hapten Conjugates Capable of Recruiting the Endogenous Antibody to Magnify the Fc Effector Immunity of Antibody for Cancer Immunotherapy.

Monoclonal antibodies (mAbs) with enhanced effector functions in cancer immunotherapy, such as complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), could improve the clinical performance. Here, we develop an mAb-hapten conjugate strategy to augment the mAb effector functions with the engagement of endogenous antibodies. An "off-the-shelf" mAb, rituximab, is site-specifically conjugated with the rhamnose (Rha) hapten to generate rituximab-Rha conjugates. The octopus-like conjugates could recruit anti-Rha antibodies onto the cancer cell surface and further form an immune complex that is able to provide multivalent Fc domains to interact with immune cells or complement protein C1q, leading to magnified ADCC and CDC simultaneously. One optimal conjugate R2 with PEG2 as a linker exhibits the most potent in vitro cancer cell killing activity and significant in vivo antitumor efficacy in a xenograft model. This is a general and cost-effective approach to generate mAb with improved effector functions that may have broad applications.

Mantle cell lymphoma with chronic lymphocytic leukemia-like features: a diagnostic mimic and pitfall.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm characterized by t(11;14) (q13;q32) and cyclin D1 overexpression in >95% of cases. Classic MCL cases are composed of a monotonous population of small- to medium-sized lymphocytes with irregular nuclear contours that are positive for cyclin D1 and SOX11 and negative for CD23 and CD200. By contrast, occasional MCL cases express CD23 and CD200 but lack SOX11 and morphologically and immunophenotypically resemble chronic lymphocytic leukemia (CLL), termed as CLL-like MCL in this study. These neoplasms pose a diagnostic challenge and are easy to be diagnosed as CLL in daily practice. We studied 14 cases of CLL-like MCL to define their clinicopathologic features and compared them with 33 traditional CLL cases. There were 8 men and 6 women with a median age of 62 years (range, 44-80). Compared with CLL, patients with CLL-like MCL have lower levels of peripheral blood and bone marrow involvement and more frequently had mutated IGHV. Immunophenotypically, CLL-like MCL often showed moderate to bright expression of B-cell antigens and surface immunoglobulin light chain, dim and partial expression of CD23 and CD200, infrequent CD43 positivity, and lack of LEF1. The overall survival of patients with CLL-like MCL was similar to that of CLL patients. In conclusion, CD23+, CD200+, and SOX11-negative MCL closely resemble CLL, both clinically and pathologically, including a similar indolent clinical course. They may pose a diagnostic challenge. However, patients with CLL-like MCL also have distinctive immunophenotypic features that are useful to distinguish these neoplasms from CLL.

[CAR-T cells in lymphomas: Current and evolving role]. / CAR-T cells dans les lymphomes : actualités récentes.

Three CD19 CAR-T cells (Yescarta®, Kymriah® and Breyanzi®), have been approved in relapsed or refractory diffuse large B cell lymphomas (DLBCL) after at least two previous lines of therapy. These immunotherapies have transformed the prognosis of these lymphomas, which can't be cured by conventional treatments. Long-term updates of registration studies as well as the first real-life data allow a better knowledge of the efficacy of these emerging therapies, their toxicity and their resistance mechanisms. These advances have also led to consider the earlier use of CAR-T cells in the therapeutic strategy and to extend it to other B lymphomas such as mantle cell and indolent lymphomas. Indeed, Yescarta® and Tecartus® have been recently approved in those malignancies, Furthermore, other strategies are being investigated to develop new CAR-T cells to target Hodgkin's lymphomas and T-cell lymphomas, although data in these settings still have to be completed. In this article, we review the latest data on the use of CAR-T cells in lymphomas.

The antibody drug conjugate VLS-101 targeting ROR1 is effective in CAR T-resistant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a rare, aggressive and incurable subtype of non-Hodgkin's B-cell lymphoma. The principal barrier is frequent clinical relapse to multiple lines of therapies, including new FDA-approved biologics and cell therapy. Brexucabtagene autoleucel, the first and only FDA approved chimeric antigen receptor (CAR) T product in MCL, demonstrated unprecedented efficacy in overcoming resistance to Bruton's tyrosine kinase inhibitors. However, relapses have inevitably occurred and once relapsed these patients display a very poor clinical outcome. Currently, there is no optional therapy specifically designed for these patients. The development of tailored and more efficacious therapies is therefore critical and represents a new medical need. We found that while the receptor tyrosine kinase-like orphan receptor 1 (ROR1) is expressed across most of the MCL cells, it is significantly elevated in CAR T-relapsed MCL tumors. To see whether this aberrant ROR1 expression contributed to CAR T resistance, we targeted ROR1 using VLS-101, a monomethyl auristatin E conjugated anti-ROR1 antibody. VLS-101 showed potent anti-MCL activity in vitro in ROR1-expressing MCL cell lines and ex vivo in primary patient samples. Importantly, VLS-101 safely induced tumor regression in PDX models resistant to CAR T-cell therapy, ibrutinib and/or venetoclax. These data advocate for targeting ROR1 as a viable approach in the treatment of ROR1-positive MCL tumors, especially those with failure to prior therapies. These data also provide strong evidence for future enrollment of post-CD19 CAR T-cell relapsed MCL patients in a first in-human phase 1b VLS-101 trial. The upcoming testing in a clinical setting will provide important insights on this new therapeutic development aiming to overcome the CAR T resistance via targeting ROR1, which is a rising unmet clinical need in MCL.

Migration and Adhesion of B-Lymphocytes to Specific Microenvironments in Mantle Cell Lymphoma: Interplay between Signaling Pathways and the Epigenetic Landscape.

Lymphocyte migration to and sequestration in specific microenvironments plays a crucial role in their differentiation and survival. Lymphocyte trafficking and homing are tightly regulated by signaling pathways and is mediated by cytokines, chemokines, cytokine/chemokine receptors and adhesion molecules. The production of cytokines and chemokines is largely controlled by transcription factors in the context of a specific epigenetic landscape. These regulatory factors are strongly interconnected, and they influence the gene expression pattern in lymphocytes, promoting processes such as cell survival. The epigenetic status of the genome plays a key role in regulating gene expression during many key biological processes, and it is becoming more evident that dysregulation of epigenetic mechanisms contributes to cancer initiation, progression and drug resistance. Here, we review the signaling pathways that regulate lymphoma cell migration and adhesion with a focus on Mantle cell lymphoma and highlight the fundamental role of epigenetic mechanisms in integrating signals at the level of gene expression throughout the genome.

SOX11, CD70, and Treg cells configure the tumor-immune microenvironment of aggressive mantle cell lymphoma.

Mantle cell lymphoma (MCL) is a mature B-cell neoplasm with a heterogeneous clinical and biological behavior. SOX11 oncogenic expression contributes to the aggressiveness of these tumors by different mechanisms, including tumor and stromal cell interactions. However, the precise composition of the immune cell microenvironment of MCL, its possible relationship to SOX11 expression, and how it may contribute to tumor behavior is not well known. Here, we performed an integrative transcriptome analysis of 730 immune-related genes combined with the immune cell phenotype analysis by immunohistochemistry in SOX11+ and SOX11- primary nodal MCL cases and non-neoplastic reactive lymph nodes. SOX11+ MCL had a significant lower T-cell intratumoral infiltration compared with negative cases. A reduced expression of MHCI/II-like and T-cell costimulation and signaling activation related transcripts was significantly associated with poor clinical outcome. Moreover, we identified CD70 as a SOX11 direct target gene, whose overexpression was induced in SOX11+, but not SOX11- tumor cells by CD40L in vitro. CD70 was overexpressed in primary SOX11+ MCL and it was associated with an immune unbalance of the tumor microenvironment characterized by increased number of effector regulatory t (Treg) cell infiltration, higher proliferation, and aggressive clinical course. CD27 was expressed with moderate to strong intensity in 76% of cases. Overall, our results suggest that SOX11 expression in MCL is associated with an immunosuppressive microenvironment characterized by CD70 overexpression in tumor cells, increased Treg cell infiltration and downmodulation of antigen processing, and presentation and T-cell activation that could promote MCL progression and represent a potential target for tailored therapies.

Localized Peritumoral AL Amyloidosis Associated With Mantle Cell Lymphoma With Plasmacytic Differentiation.

Immunoglobulin light chain (AL) amyloidosis is characterized by the deposition of amyloid fibers derived from pathologic immunoglobulin light chains. Although systemic plasma cell neoplasms are the most common cause of AL amyloidosis, a subset of cases is caused by B-cell lymphoproliferative disorders such as lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. Recently, SOX11-negative IGH hypermutated mantle cell lymphoma (MCL) is recognized to show frequent plasmacytic differentiation and indolent clinical course. Here, we report 3 cases of peritumoral AL amyloidosis associated with SOX11-negative MCL. All 3 cases showed cyclin D1 expression by immunohistochemistry and CCND1 translocation as detected by fluorescence in situ hybridization analysis. Peritumoral AL amyloidosis was observed at the biopsy sites in the gastrointestinal tract, a supraclavicular lymph node, and a cervical lymph node, and all presented with marked plasmacytic differentiation of lymphoma cells. None of the cases showed evidence of bone marrow involvement by morphology and immunophenotyping. None of the patients had distant organ involvement with systemic amyloidosis. All 3 patients had an indolent clinical course and are alive with disease at the time of the last follow-up (range: 48 to 74 mo). Our findings show that MCL with plasmacytic differentiation can cause amyloid deposition and CCND1 abnormalities should be performed in all cases of extramedullary AL amyloidosis. Recognition of indolent MCL as a cause of peritumoral AL amyloidosis may have important clinical management implications.

Single nucleotide variants in immune-response genes and the tumor microenvironment composition predict progression of mantle cell lymphoma.

BACKGROUND: There is evidence to consider that the tumor microenvironment (TME) composition associates with antitumor immune response, and may predict the outcome of various non-Hodgkin lymphoma subtypes. However, in the case of mantle cell lymphoma (MCL), a rare and aggressive disease, there is lacking a detailed study of the TME components, as well as an integrative approach among them in patients' samples. Also, from the genetic point of view, it is known that single nucleotide variants (SNVs) in immune-response genes are among important regulators of immunity. At present, it is uncertain whether SNVs in candidate immune-response genes and the TME composition are able to alter the prognosis in MCL. METHODS: We assessed a detailed TME composition in 88 MCL biopsies using immunohistochemistry, which was automatically analyzed by pixel counting (Aperio system). We also genotyped SNVs located in candidate immune-response genes (IL12A, IL2, IL10, TGFB1, TGFBR1, TGFBR2, IL17A, IL17F) in 95 MCL patients. We tested whether the SNVs could modulate the respective protein expression and TME composition in the tumor compartment. Finally, we proposed survival models in rituximab-treated patients, considering immunohistochemical and SNV models. RESULTS: High FOXP3/CD3 ratios (p = 0.001), high IL17A levels (p = 0.003) and low IL2 levels (p = 0.03) were individual immunohistochemical predictors of poorer survival. A principal component, comprising high quantities of macrophages and high Ki-67 index, also worsened outcome (p = 0.02). In the SNV model, the CC haplotype of IL10 (p < 0.01), the GG genotype of IL2 rs2069762 (p = 0.02) and the AA+AG genotypes of TGFBR2 rs3087465 (p < 0.01) were independent predictors of outcome. Finally, the GG genotype of TGFB1 rs6957 associated with lower tumor TGFß levels (p = 0.03) and less CD163+ macrophages (p = 0.01), but did not modulate patients' survival. CONCLUSIONS: Our results indicate that the TME composition has relevant biological roles in MCL. In this setting, immunohistochemical detection of T-reg cells, IL17A and IL2, coupled with SNV genotyping in IL10, TGFBR2 and IL2, may represent novel prognostic factors in this disease, following future validations.

Mantle cell lymphomas with concomitant MYC and CCND1 breakpoints are recurrently TdT positive and frequently show high-grade pathological and genetic features.

Chromosomal breakpoints involving the MYC gene locus, frequently referred to as MYC rearrangements (MYC - R+), are a diagnostic hallmark of Burkitt lymphoma and recurrent in many other subtypes of B-cell lymphomas including follicular lymphoma, diffuse large B-cell lymphoma and other high-grade B-cell lymphomas and are associated with an aggressive clinical course. In remarkable contrast, in MCL, only few MYC - R+ cases have yet been described. In the current study, we have retrospectively analysed 16 samples (MYC - R+, n = 15, MYC - R-, n = 1) from 13 patients and describe their morphological, immunophenotypic and (molecular) genetic features and clonal evolution patterns. Thirteen out of fifteen MYC - R+ samples showed a non-classical cytology including pleomorphic (centroblastic, immunoblastic), anaplastic or blastoid. MYC translocation partners were IG-loci in 4/11 and non-IG loci in 7/11 analysed cases. The involved IG-loci included IGH in 3 cases and IGL in one case. PAX5 was the non-IG partner in 2/7 patients. The MYC - R+ MCL reported herein frequently displayed characteristics associated with an aggressive clinical course including high genomic-complexity (6/7 samples), frequent deletions involving the CDKN2A locus (7/10 samples), high Ki-67 proliferation index (12/13 samples) and frequent P53 expression (13/13 samples). Of note, in 4/14 samples, SOX11 was not or only focally expressed and 3/13 samples showed focal or diffuse TdT-positivity presenting a diagnostic challenge as these features could point to a differential diagnosis of diffuse large B-cell lymphoma and/or lymphoblastic lymphoma/leukaemia.

Epcoritamab induces potent anti-tumor activity against malignant B-cells from patients with DLBCL, FL and MCL, irrespective of prior CD20 monoclonal antibody treatment.

Epcoritamab (DuoBody-CD3xCD20, GEN3013) is a novel bispecific IgG1 antibody redirecting T-cells toward CD20+ tumor cells. Here, we assessed the preclinical efficacy of epcoritamab against primary tumor cells present in the lymph node biopsies from newly diagnosed (ND) and relapsed/refractory (RR) B-NHL patients. In the presence of T-cells from a healthy donor, epcoritamab demonstrated potent activity against primary tumor cells, irrespective of prior treatments, including CD20 mAbs. Median lysis of 65, 74, and 84% were achieved in diffuse large B-cell lymphoma (n = 16), follicular lymphoma (n = 15), and mantle cell lymphoma (n = 8), respectively. Furthermore, in this allogeneic setting, we discovered that the capacity of B-cell tumors to activate T-cells was heterogeneous and showed an inverse association with their surface expression levels of the immune checkpoint molecule Herpesvirus Entry Mediator (HVEM). In the autologous setting, when lymph node (LN)-residing T-cells were the only source of effector cells, the epcoritamab-dependent cytotoxicity strongly correlated with local effector cell-to-target cell ratios. Further analyses revealed that LN-residing-derived or peripheral blood-derived T-cells of B-NHL patients, as well as heathy donor T-cells equally mediated epcoritamab-dependent cytotoxicity. These results show the promise of epcoritamab for treatment of newly-diagnosed or relapsed/refractory B-NHL patients, including those who became refractory to previous CD20-directed therapies.

Axicabtagene ciloleucel and brexucabtagene autoleucel in relapsed and refractory diffuse large B-cell and mantle cell lymphomas.

Axicabtagene ciloleucel and brexucabtagene autoleucel are anti-CD19 T-cell therapies that utilize the same second-generation chimeric antigen receptor with a CD28 costimulatory subunit. They have demonstrated high rates of response in high-risk patients with relapsed and refractory B-cell malignancies in multicenter clinical trials, including diffuse large B-cell and mantle cell lymphomas. The high clinical activity has led to the US FDA approval of axicabtagene ciloleucel for diffuse large B-cell lymphoma, and brexucabtagene autoleucel for mantle cell lymphoma. While they are highly effective, they have significant toxicities, including cytokine release syndrome and neurologic toxicities, which can be severe and require specialized management. This review will discuss the development, efficacy and safety of axicabtagene ciloleucel and brexucabtagene autoleucel in B-cell lymphomas.

LRPAP1 autoantibodies in mantle cell lymphoma are associated with superior outcome.

Low-density lipoprotein (LDL) receptor-related protein-associated protein 1 (LRPAP1) had been identified by B-cell receptor (BCR) expression cloning and subsequent protein array screening as a frequent and proliferation-inducing autoantigen of mantle cell lymphoma (MCL). Of interest, high-titered and light chain-restricted LRPAP1 autoantibodies were detected in 8 of 28 patients with MCL. In the present study, LRPAP1 autoantibodies in sera of patients treated within the Younger and Elderly trials of the European MCL Network were analyzed regarding frequency, association with disease characteristics, and prognostic impact. LRPAP1 autoantibodies were detected in 41 (13%) of 312 evaluable patients with MCL. These LRPAP1 autoantibodies belonged predominantly to the immunoglobulin G (IgG) class and were clonally light chain restricted (27 with κ light chains, 14 patients with λ light chains). Titers ranged between 1:400 and 1:3200. The presence of LRPAP1 autoantibodies was not significantly associated with any baseline clinical characteristic, however, it was associated with a superior 5-year probability for failure-free survival (FFS) of 70% (95% confidence interval [CI], 57% to 87%) vs 51% (95% CI, 44% to 58%), P = .0052; and for overall survival (OS) of 93% (95% CI, 85% to 100%) vs 68% (95% CI, 62% to 74%), P = .0142. LRPAP1-seropositive patients had a Mantle Cell Lymphoma International Prognostic Index-adjusted hazard ratio for FFS of 0.48 (95% CI 0.27-0.83, P = .0083) and for OS of 0.47 (95% CI 0.24-0.94, P = .032). LRPAP1 autoantibodies were frequently detected in a large cohort of MCL patients treated within prospective multicenter clinical trials. Our results suggest better outcomes for LRPAP1-autoantibody seropositive patients.

Histone deacetylase 8 inhibition suppresses mantle cell lymphoma viability while preserving natural killer cell function.

Mantle Cell Lymphoma (MCL) is a non-Hodgkin lymphoma with a median survival rate of five years. Standard treatment with high-dose chemotherapy plus rituximab (anti-CD20 antibody) has extended overall survival although, the disease remains incurable. Histone deacetylases (HDAC) are a family of enzymes that regulate multiple proteins and cellular pathways through post-translational modification. Broad spectrum HDAC inhibitors have shown some therapeutic promise, inducing cell cycle inhibition and apoptosis in leukemia and non-Hodgkin's lymphoma. However, the therapeutic effects of these broad-spectrum HDAC inhibitors can detrimentally dampen Natural Killer (NK) cell cytotoxicity, reduce NK viability, and downregulate activation receptors important for NK mediated anti-tumor responses. Impairment of NK function in MCL patients during therapy potentially limits therapeutic activity of rituximab. Thus, there is an unmet need to decipher specific roles of individual HDACs in order to preserve and/or enhance NK function, while, directly impairing MCL viability. We investigated the impact of HDAC8 in MCL cell lines. Inhibition or genetic loss of HDAC8 caused MCL cells to undergo apoptosis. In contrast, exposure of primary human NK cells to an HDAC8 inhibitor does not alter viability, receptor expression, or antibody dependent cellular cytotoxicity (ADCC). However, an increase in effector cytokine interferon-gamma (IFNγ) producing NK cells was observed in response to HDAC8 inhibition. Taken together these data suggest that selective HDAC8 inhibitors may simultaneously preserve NK functional activity, while impairing MCL tumor growth, establishing a rationale for future clinical evaluation.

Anti-human CD99 antibody exerts potent antitumor effects in mantle cell lymphoma.

CD99 is a surface molecule expressed on various cell types including cancer cells. Expression of CD99 on multiple myeloma is associated with CCND1-IGH fusion/t(11;14). This translocation has been reported to be a genetic hallmark of mantle cell lymphoma (MCL). MCL is characterized by overexpression of cyclin D1 and high tumor proliferation. In this study, high expression of CD99 on MCL cell lines was confirmed. Our generated anti-CD99 monoclonal antibody (mAb), termed MT99/3, exerted potent antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) activities against mantle B-cell lymphoma without direct cytotoxic effects. The anti-tumor activities of mAb MT99/3 were more effective in MCL than in other B-cell lymphomas. Moreover, in a mouse xenograft model using Z138 MCL cell line, treatment of mAb MT99/3 reduced tumor development and growth. Our study indicated that mAb MT99/3 is a promising immunotherapeutic candidate for mantle cell lymphoma therapy.

Immune-related protein signature in serum stratify relapsed mantle cell lymphoma patients based on risk.

BACKGROUND: Response to modern treatment strategies, which combine cytotoxic compounds with immune stimulatory agents and targeted treatment is highly variable among MCL patients. Thus, providing prognostic and predictive markers for risk adapted therapy is warranted and molecular information that can help in patient stratification is a necessity. In relapsed MCL, biopsies are rarely available and molecular information from tumor tissue is often lacking. Today, the main tool to access risk is the MCL international prognostic index (MIPI), which does not include detailed biological information of relevance for different treatment options. To enable continuous monitoring of patients, non-invasive companion diagnostic tools are needed which can further reduce cost and patient distress and enable efficient measurements of biological markers. METHODS: We have assessed if serum-based protein profiling can identify immune related proteins that stratify relapsed MCL patients based on risk. Overall, 371 scFv targeting 158 proteins were assessed using an antibody microarray platform. We profiled patients (n = 44) who had been treated within the MCL6-Philemon trial combining targeted and immune-modulatory treatment. RESULTS: The downstream processing led to the identification of the relapsed immune signature (RIS) consisting of 11 proteins with potential to stratify patients with long and short overall survival (OS). Moreover, in this population, MIPI alone failed to separate high, intermediate and low risk patients, but a combined index based on MIPI together with RIS, MIPIris, showed improved performance and significantly stratified all three risk groups based on OS. CONCLUSIONS: Our results show that addition of biological parameters to previous prognostic indices improves patient stratification among patients treated with BTK inhibitor triplet combination, particularly, in the identification of an extreme high risk group.