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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The first-generation BsMAbs were known counterintuitively as tri-functional antibodies (or “Triomabs”). They consisted of two heavy and two light chains, one from each of two different antibodies, and with the two different Fab regions directed against two different antigens (Figure 7.51A). The Fc region (the stem) was made up from the two heavy chains and formed a third binding site, thus giving rise to the Triomab name. Diagram of three different formats of bispecific antibodies. A. A tri-functional antibody, B. A chemically linked Fab (or F(ab’)2), C. A bispecific T-cell engager (or BiTE). The parts of the two different antibodies contributing to the structures are colored blue and green.
Lymphocyte and plasma cell malignancies
Published in Gabriel Virella, Medical Immunology, 2019
Juan Carlos Varela, Gabriel Virella
The treatment of ALL has significantly changed over the past 20 years. In general, children, adolescents, and young adults (<40 years old) with ALL can be treated, and in many instances cured, with just chemotherapy. Chemotherapy regimens for ALL are complex and have several “phases” of treatment expanding several months. Adults >40 years old are treated with induction chemotherapy followed by an allogeneic stem cell transplant for those patients who are eligible. This combination of chemotherapy and transplant is the only known curative treatment for ALL in adults. The treatment of relapsed/refractory ALL in children and adults has seen the most dramatic advances with the development of immune therapies targeting CD19, a molecule expressed by the majority of ALL cells. The two main immunotherapies used for the treatment of ALL are chimeric antigen receptor T cells (CAR T cells) and blinatumomab, a bispecific T-cell engager (BiTe). (See Chapter 26 for more information regarding these therapies.)
Non-Hodgkin Lymphoma
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The enhanced understanding of the genetic events and immune microenvironment has facilitated a greater application of targeted and immunological therapies for patients with relapsed and rituximab refractory FL. In such patients, earlier studies with the BTK inhibitor, ibrutinib, resulted in a modest efficacy, possibly due to the presence of coexisting mutations, such as CARD11, which are now considered to confer resistance to ibrutinib. Several novel anti-CD20 monoclonal antibodies, such as veltuzumab, as monotherapy and in combination with the anti-CD74, milatuzumab and ocrartuzumab (AME-133) are ongoing. There appears to be greater promise for epigentically targeted therapies (such as tazemetostat, an EZH2 inhibitor) and vorinostat (a histone deactylase inhibitor). Studies are also testing the inclusion of immune checkpoint inhibitors and CAR T-cell specific for CD19, a differentiation antigen expressed in B-cells and B lineage malignancies. The next generation of novel antibody-based therapies, such as bispecific antibodies, which combine the specificity of two antibodies, so they can bind to different antigens. Bispecific T-cell engager (BiTE) binds CD3 on T-cells and an antigen on tumour cells to activate T-cells to kill the cancer cells. The first-in-class BiTE antibody, blinatumomab, which specifically targets CD19 on B-cells, was approved in 2014 for clinical use in patients with relapsed or refractory ALL and is now being tested in FL, and preliminary results when the drug is administered at very low doses are encouraging.
Longitudinal immune monitoring of patients with resectable esophageal adenocarcinoma treated with Neoadjuvant PD-L1 checkpoint inhibition
Published in OncoImmunology, 2023
Tom van den Ende, Aiarpi Ezdoglian, Lisanne M. Baas, Joyce Bakker, Sinéad M. Lougheed, Micaela Harrasser, Cynthia Waasdorp, Mark I. van Berge Henegouwen, Maarten C.C.M. Hulshof, Nadia Haj Mohammad, Richard van Hillegersberg, Stella Mook, Conny J. van der Laken, Nicole C.T. van Grieken, Sarah Derks, Maarten F. Bijlsma, Hanneke W.M. van Laarhoven, Tanja D. de Gruijl
In a non-randomized phase II study (PERFECT) we investigated whether the addition of an immune checkpoint inhibitor (ICI), atezolizumab (anti-PD-L1), to nCRT enhanced the efficacy of neoadjuvant treatment.4 Treatment was feasible but there was no significant difference in response or survival compared to a propensity matched nCRT cohort.4 However, there is a strong relationship between pathological complete response (pCR) and long-term outcome, not only for chemoradiation in esophageal cancer but also for neoadjuvant ICI.5,6 Identifying factors related to pathological response could lead to better patient selection through biomarkers or identify mechanisms of treatment resistance. In several tumor types flow cytometry of peripheral blood mononuclear cells (PBMCs) has identified a number of checkpoint molecules and cell types which are altered under the influence of systemic therapy.7,8 In patients with lung cancer and melanoma treated with anti-PD-1 or anti-CTLA-4 immunotherapy, complete and partial radiological responders had higher expression of PD-1 on CD8+ on-treatment or more baseline CD69+ natural killer (NK) cells compared to non-responders.9,10 In poor responders higher frequencies of inhibitory myeloid-derived suppressor cells (MDSCs) or regulatory T cells (Tregs) were found in patients treated with an anti-CTLA-4 antibody (melanoma) or a bi-specific T cell engager (B-precursor acute lymphoblastic leukemia).11,12 Flow cytometry of immune cells thus provides important clues for response and resistance mechanisms in the immunotherapy setting.
Novel Fab-peptide-HLA-I fusion proteins for redirecting pre-existing anti-CMV T cell immunity to selectively eliminate carcinoma cells
Published in OncoImmunology, 2023
Isabel Britsch, Anne P. van Wijngaarden, Xiurong Ke, Mark. A.J.M. Hendriks, Douwe F. Samplonius, Emily M. Ploeg, Wijnand Helfrich
Here, we demonstrate the potent capacity of EpCAM-ReTARGpp65 to selectively redirect the cytotoxic potential of HLA-B × 07:02-restricted TPR-specific anti-CMV CD8pos T cells toward various EpCAM-expressing cancer cell lines and primary patient-derived carcinoma cells. Importantly, during EpCAM-ReTARGpp65-mediated elimination of cancer cells, T cell-secreted cytokine levels did not appear to be excessively elevated. In contrast, analogous treatment with equimolar amounts of the EpCAM/CD3-directed bispecific T cell engager solitomab resulted in excessive release of IFNγ, a feature commonly associated with cytokine-release syndrome. Combinatorial treatment of carcinoma cells with EpCAM-ReTARGpp65 and EGFR-ReTARGIE-1 strongly potentiated cancer cell elimination, likely due to the concurrent cytolytic action of the respective cognate anti-CMV CD8pos T cell clones. Importantly, during combinatorial treatment, T cell-secreted cytokine levels were only slightly elevated compared to single-agent treatment.
Fc-based Duokines: dual-acting costimulatory molecules comprising TNFSF ligands in the single-chain format fused to a heterodimerizing Fc (scDk-Fc)
Published in OncoImmunology, 2022
Nadine Aschmoneit, Katharina Kocher, Martin Siegemund, Martina S. Lutz, Lennart Kühl, Oliver Seifert, Roland E. Kontermann
As an alternative to antibodies, soluble ligands can serve as activators of costimulatory signals. Conversion of the homotrimeric members of the TNFSF into a single-chain format further fused to an antigen-binding moiety of an antibody, e.g. a single-chain Fv (scFv) fragment, has been shown to successfully mimic cell surface-displayed activity for target-dependent T-cell activation.12 Furthermore, we have recently developed a novel approach allowing simultaneous binding and activation of two different costimulatory receptors. This was achieved by combining two different members of the TNFSF into one molecule connecting either single subunits of two ligands (so-called Duokines, Dk) or single-chain derivatives of the ligand (single-chain Duokines, scDk) by flexible linkers.13 We have demonstrated that these dual-acting costimulatory molecules can activate two different receptor types either on the same cell (i.e. acting in cis) or on different cell types (i.e. acting in trans). In combination with a bispecific T-cell engager, these molecules mediated an enhanced T-cell proliferation in vitro and showed promising anti-tumor effects in vivo.13