27 december 2023: Bron: Biomarker Research volume 9, Article number: 38 (2021)

BiTE = Bispecifieke T-cel-engager  medicijnen en behandelingen blijkt een hoopvolle nieuwe variant van immuuntherapie met gemoduleerde CAR-T cellen bij de behandeling van kanker. Ook bij vormen van kanker met solide tumoren. 

Bi-specifieke antilichamen (BiTE) zijn opgebouwd uit twee verschillende antilichamen waardoor ze twee verschillende soorten antigenen kunnen herkennen om een immuunrespons in het lichaam op gang te brengen. Dat betekent dat bi-specifieke antilichamen het afweersysteem van de patiënt activeren om de ziekte te bestrijden.

In een reviewstudie wordt een overzicht gegeven van de ontwikkelingen op dit gebied (abstract staat verderop in dit artikel).

Hier een stuk tekst uit de introductie van de studie vertaald:

Op T-cellen gebaseerde immuuntherapieën bij kanker hebben de klinische praktijk van kankerbehandeling getransformeerd door T-cellen te targeten en te mobiliseren om kwaadaardige tumorcellen te vernietigen.
Afhankelijk van de werkingsmechanismen kunnen op T-cellen gebaseerde vormen van immuuntherapieën hoofdzakelijk in twee klassen worden verdeeld: de ene tegen immuunsuppressieve factoren, vertegenwoordigd door Anti-PD medicijnen - checkpointremmers (ICI's).
De andere vorm is gericht op immuunstimulerende routes, vertegenwoordigd door chimere antigeenreceptor (CAR) T. cellen en op T-cel-aangrijpende bispecifieke antilichamen (bsAbs). [1,2,3]

Anti-PD medicijnen - checkpointremmers (ICI's) hebben een revolutie teweeggebracht in de behandeling van kanker in de kliniek, vooral bij verschillende gevorderde solide tumoren, bijvoorbeeld melanoom en niet-kleincellige longkanker. [4,5,6,7]  
Ze belemmeren de immuunontsnapping van de tumor door belangrijke immunosuppressieve moleculen zoals geprogrammeerde celdood 1 (PD-1) en zijn ligand (PD-L1) te blokkeren en de ‘rem’ van cytotoxische T-cellen vrij te geven om tumorcellen te elimineren. Maar de werking van Anti-PD medicijnen - checkpointremmers (ICI's) blijven beperkt. [8]  
Een belangrijke reden hiervoor is het ontbreken van een voldoende aantal tumor-infiltrerende immuuncellen (TIL's), voornamelijk T-cellen, op de tumorplaats, die een koud fenotype wordt genoemd [9].

CAR T-celtherapie is een nieuw ontwikkelde adoptieve celtherapie door T-cellen genetisch te manipuleren om een CAR tot expressie te brengen die bestaat uit intracellulaire T-cel-signaleringsdomeinen en een extracellulaire antigeenherkenningsstructuur die zich richt op tumor-geassocieerde antigenen (TAA's), waardoor T-cellen worden omgeleid en geactiveerd naar kwaadaardige cellen specifiek uitroeien. [10]

De bereiding van CAR T-cellen omvat voornamelijk isolatie van T-cellen bij patiënten, genetische modificatie van T-cellen, expansie van T-cellen in vitro en infusie van bewerkte T-cellen bij patiënten, wat echter een complex en tijdrovend proces is [11].

De andere alternatieve benadering om T-cellen om te leiden naar doelcellen is T-cel-aangrijpende bsAbs met unieke functie-aansprekende TAA's op kankercellen en celoppervlaktemoleculen op T-cellen. Bispecifieke T-cel-engager (BiTE) onderscheidt zich als een nieuwe subklasse van T-cel-aangrijpende bsAbs met veelbelovende klinische resultaten bij de behandeling van kanker. En de vergelijking van deze drie op T-cellen gebaseerde immuuntherapieën is samengevat in Tabel 1.

Een afbeelding uit het studieverslag dat het werkings mechanisme van een Bi-specifieke antilichamen (BiTE) verbeeldt:

figure 1
The schematic representation of structure and mechanism of action of canonical bispecific T-cell engager (BiTE). mAb: Monoclonal antibody; VH: Heavy chain variable region; VL: Light chain variable region; TAA: Tumor-associated antigen

De onderzoekers concluderen:

Conclusies:

Naarmate het landschap van T-cellen en hun rol in de immuniteit tegen kanker evolueert, heeft de ontwikkeling van op T-cellen gebaseerde immuuntherapieën het afgelopen decennium een enorme doorbraak bereikt. In het bijzonder hebben de BiTE-antilichamen die T-cellen omleiden om tumorcellen te doden, gunstige klinische resultaten vertoond bij R/R-hematopoëtische maligniteiten, evenals bij solide tumoren met voorlopig bewijs van klinische voordelen.
Er blijft echter een aanzienlijk aantal patiënten die resistent zijn tegen de BiTE-therapie en geen duurzame respons kunnen bereiken.
Huidig onderzoek heeft aangetoond dat antigeenverlies en immunosuppressieve factoren, vooral de opregulatie van remmende checkpointmoleculen, de twee belangrijkste mechanismen zijn, die verantwoordelijk zijn voor het mislukken van de behandeling.
Daarom worden momenteel strategieën met betrekking tot het verbeteren van BiTE-constructies en het ontwikkelen van nieuwe T-cel-engager-antilichamen met hogere antigeen-aviditeiten en meerdere doelwitten onderzocht in een reeks preklinische en klinische onderzoeken, evenals combinatietherapieën met BiTE-antilichamen en andere therapeutische benaderingen.
Naast T-cellen krijgen aangeboren cel- of aangeboren-achtige cel-engagers die zich richten op aangeboren immuniteit steeds meer aandacht en hebben ze krachtige antitumoractiviteit getoond bij verschillende vormen van kanker, wat een oriëntatie op de toekomst weerspiegelt.

Voor het volledige studierapport dat heel uitgebreid ingaat op de verschillende vormen van T-cel-aangrijpende bispecifieke antilichamen (bsAbs) en ook de lopende studies noemt en studies in combinatie met chemotherapie of andere reguliere behandelingen is gratis in te zien.  

Klik op de titel van het abstract:

The landscape of bispecific T cell engager in cancer treatment

Biomarker Research volume 9, Article number: 38 (2021) Cite this article

Abstract

T cell-based immunotherapies have revolutionized treatment paradigms in various cancers, however, limited response rates secondary to lack of significant T-cell infiltration in the tumor site remain a major problem. To address this limitation, strategies for redirecting T cells to treat cancer are being intensively investigated, while the bispecific T cell engager (BiTE) therapy constitutes one of the most promising therapeutic approaches. BiTE is a bispecific antibody construct with a unique function, simultaneously binding an antigen on tumor cells and a surface molecule on T cells to induce tumor lysis. BiTE therapy represented by blinatumomab has achieved impressive efficacy in the treatment of B cell malignancies. However, major mechanisms of resistance to BiTE therapy are associated with antigen loss and immunosuppressive factors such as the upregulation of immune checkpoints. Thus, modification of antibody constructs and searching for combination strategies designed to further enhance treatment efficacy as well as reduce toxicity has become an urgent issue, especially for solid tumors in which response to BiTE therapy is always poor. In particular, immunotherapies focusing on innate immunity have attracted increasing interest and have shown promising anti-tumor activity by engaging innate cells or innate-like cells, which can be used alone or complement current therapies. In this review, we depict the landscape of BiTE therapy, including clinical advances with potential response predictors, challenges of treatment toxicity and resistance, and developments of novel immune cell-based engager therapy.


Availability of data and materials

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Acknowledgements

I would like to thank my supervisor, Dr. Meng, for her guidance through each stage of the process.

Funding

The study was funded by the National Natural Science Foundation of China (No.81972796 and 81972863), the National Key Research and Development Project (2018YFC1313200), the Innovation Project of Shandong Academy of Medical Sciences (2019–04), the Natural Science Foundation of Shandong (No.ZR2019MH010), and the Academic Promotion Program of Shandong First Medical University (2019ZL002).

Author information

Authors and Affiliations

  1. Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

    Shujie Zhou, Xiangjiao Meng & Jinming Yu

  2. Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong First Medical University, Jinan, Shandong, China

    Shujie Zhou, Fei Ren, Xiangjiao Meng & Jinming Yu

  3. Department of Oncology, Yuncheng Honesty Hospital, Heze, Shandong, China

    Mingguo Liu

  4. Department of Radiation Oncology, Shandong Cancer Hospital affiliated to Shandong University, Jinan, Shandong, China

    Xiangjiao Meng

Contributions

Shujie Zhou: Contributed to Writing - Original Draft, Investigation, and Resources. Mingguo Liu: Contributed to Resources. Fei Ren: Contributed to Resources. Jinming Yu: Contributed to the Writing - Review & Editing and Funding acquisition. Xiangjiao Meng: Contributed to Study design, Supervision, and Writing - Review & Editing. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xiangjiao Meng.

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Competing interests

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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BiTE = Bispecifieke T-cel-engager, immuuntherapie, CAR-T celtherapie, vormen van kanker, solide tumoren, reviewstudie


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