Editorial

7 pages, 251 KiB

Open AccessEditorial

Immunotherapies in Non-Hodgkin’s Lymphoma

by Christine Bezombes and Patricia Pérez-Galán

Cancers 2021, 13(14), 3625; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13143625 - 20 Jul 2021

Cited by 4 | Viewed by 1974

Immune-based therapies mobilize the immune system to promote or restore an effective antitumor immune response [...] Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

Research

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17 pages, 2657 KiB

Open AccessArticle

Clinical and Product Features Associated with Outcome of DLBCL Patients to CD19-Targeted CAR T-Cell Therapy

by Sylvain Lamure, François Van Laethem, Delphine De Verbizier, Claire Lozano, Eve Gehlkopf, Jean-Jacques Tudesq, Chris Serrand, Mehdi Benzaoui, Tarik Kanouni, Adeline Quintard, John De Vos, Emmanuelle Tchernonog, Laura Platon, Xavier Ayrignac, Patrice Ceballos, Anne Sirvent, Mickael François, Hanane Guedon, Philippe Quittet, Cedric Mongellaz, Aurélie Conte, Charles Herbaux, Caroline Bret, Naomi Taylor, Valérie Dardalhon and Guillaume Cartron Show full author list Hide full author list

Cancers 2021, 13(17), 4279; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174279 - 25 Aug 2021

Cited by 18 | Viewed by 4392

Abstract

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were [...] Read more.

CD19-directed CAR T-cells have been remarkably successful in treating patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and transformed follicular lymphoma (t-FL). In this cohort study, we treated 60 patients with axicabtagene ciloleucel or tisagenlecleucel. Complete and partial metabolic responses (CMR/PMR) were obtained in 40% and 23% of patients, respectively. After 6.9 months of median follow-up, median progression-free survival (mPFS) and overall survival (mOS) were estimated at 3.1 and 12.3 months, respectively. Statistical analyses revealed that CMR, PFS, and OS were all significantly associated with age-adjusted international prognostic index (aaIPI, p < 0.05). T-cell subset phenotypes in the apheresis product tended to correlate with PFS. Within the final product, increased percentages of both CD4 and CD8 CAR⁺ effector memory cells (p = 0.02 and 0.01) were significantly associated with CMR. Furthermore, higher CMR/PMR rates were observed in patients with a higher maximal in vivo expansion of CAR T-cells (p = 0.05) and lower expression of the LAG3 and Tim3 markers of exhaustion phenotype (p = 0.01 and p = 0.04). Thus, we find that aaIPI at the time of infusion, phenotype of the CAR T product, in vivo CAR T-cell expansion, and low levels of LAG3/Tim3 are associated with the efficacy of CAR T-cell therapy in DLBCL patients. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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15 pages, 1626 KiB

Open AccessArticle

Co-Stimulatory versus Cell Death Aspects of Agonistic CD40 Monoclonal Antibody Selicrelumab in Chronic Lymphocytic Leukemia

by Raquel Delgado, Karoline Kielbassa, Johanna ter Burg, Christian Klein, Christine Trumpfheller, Koen de Heer, Arnon P. Kater and Eric Eldering

Cancers 2021, 13(12), 3084; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13123084 - 21 Jun 2021

Cited by 5 | Viewed by 3502

Abstract

Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular [...] Read more.

Objectives: Chronic lymphocytic leukemia (CLL) is a common form of leukemia with a heterogeneous clinical course that remains incurable due to the development of therapy resistance. In lymph node proliferation centers, signals from the microenvironment such as CD40 ligation through interaction with follicular T helper cells shield CLL cells from apoptosis. Previous observations have shown that, despite CD40-induced changes in apoptotic mediators resulting in cell survival, CD40 activation also increases sensitivity to cell death by CD20 mAbs rituximab and obinutuzumab. To further investigate these observations, we here studied the activity of the fully human agonistic CD40 mAb selicrelumab in primary CLL cells in relation to cell activation, induced pro-survival profile, and sensitization for cell death by aCD20 mAbs, in vitro. Methods: CLL cells from peripheral blood were isolated by the Ficoll density method. The expression of activation markers and cytokine production following CD40 stimulation was quantified by flow cytometry and ELISA. The anti-apoptotic profile of CLL induced by stimulation was evaluated by the expression of BCL-2 proteins with Western blot, and resistance to venetoclax with flow cytometry. Cell death induced by the combination of selicrelumab and aCD20 mAbs was quantified by flow cytometry. Results: CLL cells treated with selicrelumab upregulated co-stimulatory molecules such as CD86, TNF-α and death receptor CD95/Fas. In contrast to the CD40 ligand-transfected NIH3T3 cells, induction of resistance to venetoclax by selicrelumab was very moderate. Importantly, selicrelumab stimulation positively sensitized CLL cells to CD20-induced cell death, comparable to CD40 ligand-transfected NIH3T3 cells. Conclusions: Taken together, these novel insights into selicrelumab-stimulatory effects in CLL may be considered for developing new therapeutic strategies, particularly in combination with obinutuzumab. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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Review

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18 pages, 1805 KiB

Open AccessReview

Cellular Therapy Updates in B-Cell Lymphoma: The State of the CAR-T

by Zachary D. Crees and Armin Ghobadi

Cancers 2021, 13(20), 5181; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205181 - 15 Oct 2021

Cited by 11 | Viewed by 3212

Abstract

Non-Hodgkin Lymphoma accounts for >460,000 cases and >240,000 deaths globally and >77,000 cases and >20,000 deaths in the U.S. annually, with ~85% of cases being B-cell malignancies. Until recently, patients with relapsed/refractory B-cell lymphoma following standard chemotherapy in combination with anti-CD20 monoclonal antibodies [...] Read more.

Non-Hodgkin Lymphoma accounts for >460,000 cases and >240,000 deaths globally and >77,000 cases and >20,000 deaths in the U.S. annually, with ~85% of cases being B-cell malignancies. Until recently, patients with relapsed/refractory B-cell lymphoma following standard chemotherapy in combination with anti-CD20 monoclonal antibodies and autologous stem cell transplantation experienced a median overall survival (OS) of <6 months. However, with the approval of four different CD-19 CAR-T therapies between 2017 and 2021, approximately 60–80% of patients receiving CAR-T therapy now achieve an objective response with >3 years median OS. Here, we review the current state of the art of CD19 CAR-T therapies for B-cell lymphomas, focusing on current updates in US FDA-approved products, along with their associated efficacy and toxicities. Lastly, we highlight a selection of promising clinical developments in the field, including various novel strategies to increase CAR-T therapy efficacy while mitigating toxicity. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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17 pages, 3973 KiB

Open AccessReview

Emerging Landscape of Immunotherapy for Primary Central Nervous System Lymphoma

by Marion Alcantara, Jaime Fuentealba and Carole Soussain

Cancers 2021, 13(20), 5061; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13205061 - 10 Oct 2021

Cited by 10 | Viewed by 2751

Abstract

Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas [...] Read more.

Primary central nervous system lymphoma (PCNSL) is, mainly, a diffuse large B-cell lymphoma (DLBCL) with a non-germinal center B-cell (non-GCB) origin. It is associated with a poor prognosis and an unmet medical need. Immunotherapy has emerged as one of the most promising areas of research and is now part of the standard treatment for many solid and hematologic tumors. This new class of therapy generated great enthusiasm for the treatment of relapsed/refractory PCNSL. Here, we discuss the challenges of immunotherapy for PCNSL represented by the lymphoma cell itself and the specific immune brain microenvironment. We review the current clinical development from the anti-CD20 monoclonal antibody to CAR-T cells, as well as immune checkpoint inhibitors and targeted therapies with off-tumor effects on the brain microenvironment. Perspectives for improving the efficacy of immunotherapies and optimizing their therapeutic role in PCNSL are suggested. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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24 pages, 1716 KiB

Open AccessFeature PaperReview

The PD-1/PD-L1 Checkpoint in Normal Germinal Centers and Diffuse Large B-Cell Lymphomas

by Marcos Garcia-Lacarte, Sara C. Grijalba, Javier Melchor, Adrián Arnaiz-Leché and Sergio Roa

Cancers 2021, 13(18), 4683; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184683 - 18 Sep 2021

Cited by 10 | Viewed by 4079

Abstract

Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells [...] Read more.

Besides a recognized role of PD-1/PD-L1 checkpoint in anti-tumour immune evasion, there is accumulating evidence that PD-1/PD-L1 interactions between B and T cells also play an important role in normal germinal center (GC) reactions. Even when smaller in number, T follicular helper cells (T_FH) and regulatory T (T_FR) or B (Breg) cells are involved in positive selection of GC B cells and may result critical in the lymphoma microenvironment. Here, we discuss a role of PD-1/PD-L1 during tumour evolution in diffuse large B cell lymphoma (DLBCL), a paradigm of GC-derived lymphomagenesis. We depict a progression model, in two phases, where malignant B cells take advantage of positive selection signals derived from correct antigen-presentation and PD-1/PD-L1 inter-cellular crosstalks to survive and initiate tumour expansion. Later, a constant pressure for the accumulation of genetic/epigenetic alterations facilitates that DLBCL cells exhibit higher PD-L1 levels and capacity to secrete IL-10, resembling Breg-like features. As a result, a complex immunosuppressive microenvironment is established where DLBCL cells sustain proliferation and survival by impairing regulatory control of T_FR cells and limiting IL-21-mediated anti-tumour functions of T_FH cells and maximize the use of PD-1/PD-L1 signaling to escape from CD8⁺ cytotoxic activity. Integration of these molecular and cellular addictions into a framework may contribute to the better understanding of the lymphoma microenvironment and contribute to the rationale for novel PD-1/PD-L1-based combinational immunotherapies in DLBCL. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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13 pages, 7158 KiB

Open AccessReview

CAR-T after Stem Cell Transplantation in B-Cell Lymphoproliferative Disorders: Are They Really Autologous or Allogenic Cell Therapies?

by Ariadna Bartoló-Ibars, Mireia Uribe-Herranz, Guillermo Muñoz-Sánchez, Cristina Arnaldos-Pérez, Valentín Ortiz-Maldonado, Álvaro Urbano-Ispizua, Mariona Pascal and Manel Juan

Cancers 2021, 13(18), 4664; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13184664 - 17 Sep 2021

Cited by 10 | Viewed by 2479

Abstract

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is one of the standard treatments for B-cell lymphoproliferative disorders; however, deep relapses are common after an allo-HSCT, and it is associated with poor prognosis. A successful approach to overcome these relapses is to exploit the body’s [...] Read more.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is one of the standard treatments for B-cell lymphoproliferative disorders; however, deep relapses are common after an allo-HSCT, and it is associated with poor prognosis. A successful approach to overcome these relapses is to exploit the body’s own immune system with chimeric antigen receptor (CAR) T-cells. These two approaches are potentially combinatorial for treating R/R B-cell lymphoproliferative disorders. Several clinical trials have described different scenarios in which allo-HSCT and CAR-T are successively combined. Further, for all transplanted patients, assessment of chimerism is important to evaluate the engraftment success. Nonetheless, for those patients who previously received an allo-HSCT there is no monitorization of chimerism before manufacturing CAR T-cells. In this review, we focus on allo-HSCT and CAR-T treatments and the different sources of T-cells for manufacturing CAR T-cells. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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13 pages, 265 KiB

Open AccessReview

T-cell Redirecting Therapies for the Treatment of B-cell Lymphomas: Recent Advances

by Ondine Messéant, Roch Houot and Guillaume Manson

Cancers 2021, 13(17), 4274; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13174274 - 25 Aug 2021

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Abstract

T-cell specificity can be redirected against tumor antigens either ex vivo using engineered chimeric antigen receptor (CAR) T-cells or in vivo by bridging natural T-cells and tumor cells with bispecific T-cell engager (TCE) antibodies. Currently, four CAR T-cells have been approved by the [...] Read more.

T-cell specificity can be redirected against tumor antigens either ex vivo using engineered chimeric antigen receptor (CAR) T-cells or in vivo by bridging natural T-cells and tumor cells with bispecific T-cell engager (TCE) antibodies. Currently, four CAR T-cells have been approved by the FDA for the treatment of B-cell lymphomas, including diffuse large B cell lymphomas (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). No TCE have yet been approved for the treatment of B-cell lymphomas. However, at least four of them are in clinical development and show promising activity. Here, we review the most recent advances of CAR T-cells and TCE in the treatment of B-cell lymphomas. Full article

(This article belongs to the Special Issue Immunotherapy in B-cell Non-Hodgkin Lymphomas)

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