Old and New Targets for Immunotherapy of B Cell Acute
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Acta Haematologica Polonica 2021 Number 4, Volume 52, pages 291–299 REVIEW ARTICLE DOI: 10.5603/AHP.2021.0056 ISSN 0001–5814 e-ISSN 2300–7117 Old and new targets for immunotherapy of B cell acute lymphoblastic leukemia Małgorzata Firczuk ●iD Department of Immunology, Medical University of Warsaw, Warsaw, Poland Abstract B cell-specific antigens such as CD20 and CD19 are the leading examples of clinically utilized targets for cancer im- munotherapy. Rituximab, the anti-CD20 monoclonal antibody (mAb) approved for the treatment of B cell lymphoma in 1997, was the earliest mAb drug ever registered in cancer immunotherapy. The clinical success of chimeric antigen receptor (CAR)-modified T cells has been demonstrated in patients with B cell acute lymphoblastic leukemia (B-ALL), and CD19-directed CAR-T cells were the first CAR therapy ever approved to treat cancer patients. While surface antigen- targeting immunotherapies play a significant role in the therapy of B-ALL, in particular in the treatment of relapsed and refractory patients, they have some limitations and face continuous challenges. Herein, I review the types of antigen- specific immunotherapies that are used in the treatment of B-ALL, including naked mAbs, antibody-drug conjugates, B cell-specific T cell engagers, and CAR-modified T cells. I discuss the requirements for good immunotherapy targets and summarize the main methods used to identify novel putative targets. I present an overview of B cell-specific and non-B cell-specific target antigens, both already used in clinics and tested in preclinical models. I also discuss limita- tions of current B-ALL immunotherapy, attempts to overcome these limitations, and future directions of immunotherapy research. Key words: acute lymphoblastic leukemia, B cell, immunotherapy, antigen, target, CD19, CD22, CD20, CD72 Acta Haematologica Polonica 2021; 52, 4: 291–299 Introduction many patients relapse with CD19-negative disease [1, 2]. Other B cell-specific antigens such as CD22 and CD20 are Surface antigen-targeted immunotherapies were first already available as second-line therapies of CD19-nega- introduced in the treatment of B cell malignancies. The tive relapses and their efficacy has been tested in clinical availability of B cell-specific target antigens such as CD19, trials [3, 4]. However, emerging results of these trials are CD20 and CD22 that are not expressed in other tissues revealing at best transient responses, hence novel target has greatly contributed to success. CD19 is the main target antigens need to be identified and verified. for chimeric antigen receptor (CAR) T cell immunotherapy B-ALL is a heterogeneous disease with dozens of ge- and for blinatumomab, a bispecific T cell engager (BiTE). netic abnormalities identified to date, and it develops in Both therapies are already approved for the treatment both children and adults. Although the survival progno- of relapsed/refractory (R/R) B cell acute lymphoblastic sis is good for pediatric B-ALL (~90%), the treatment out- leukemia (B-ALL). Although CD19 CAR-T cells have shown come in adults is much worse (40–50% overall survival) unprecedented response rates, exceeding 80% in R/R [5]. Patients harboring specific genetic translocations re- B-ALL patients, the durability of response is limited, and spond poorly to conventional therapy but also to modern Address for correspondence: Małgorzata Firczuk, Copyright © 2021 Department of Immunology, Medical University of Warsaw, Nielubowicza 5, The Polish Society of Haematologists and Transfusiologists, F Building, 02–097 Warsaw, Poland, phone +48 22 599 21 98, Insitute of Haematology and Transfusion Medicine. e-mail: [email protected] All rights reserved. Received: 24.05.2021 Accepted: 27.05.2021 This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. www.journals.viamedica.pl/acta_haematologica_polonica 291291 Acta Haematologica Polonica 2021, vol. 52, no. 4 immunotherapies. The subtype with the poorest outcome modified ex vivo with CARs, and infused back into the pa- is mixed lineage leukemia-rearranged B-ALL (MLLr B-ALL), tient’s circulation, where they specifically recognize cells which frequently escapes CD19-targeted immunotherapy expressing target antigens, mainly leukemic cells. Impor- due to lineage switch from MLLr B-ALL to MLLr acute my- tantly, the recognition of malignant cells by CAR-T cells and eloid leukemia (AML), with a loss of B cell phenotype-as- induction of the cytotoxic responses are major histocom- sociated markers [6–9]. This precludes the use of B cell- patibility complex (MHC)-independent. The construction of specific antigens as immunotherapy targets and encourag- CAR molecules, e.g. the choice of costimulatory domains es the selection of novel candidates as alternative targets as well as types of hinge and transmembrane domains, for immunotherapy. significantly affect CAR-T cell functionality [14]. In this review, I describe the types of antigen-specific Although antigen-targeted immunotherapy is more immunotherapy currently used in the treatment of B-ALL. specific than conventional chemotherapy, adverse side- I define the features of appropriate immunotherapy targets, effects associated with CAR-T cell and BiTE therapy have and list ways to identify novel targets for immunotherapy. In been frequently reported. B cell aplasia, a direct conse- addition, I summarize the target antigens already utilized quence of on-target off-tumor toxicity, impairs antibody in R/R B-ALL therapy as well as novel, alternative targets production and increases susceptibility to infection, but is tested in preclinical models. Finally, I discuss the limita- manageable with immunoglobulin infusion. A treatment- tions and challenges of B-ALL immunotherapy. induced life-threatening complication is cytokine release syndrome (CRS), which leads to multiple organ dysfunc- Types of antigen-specific immunotherapy tion and neurotoxicity [15]. This can be mitigated with the employed in B-ALL use of corticosteroids and tocilizumab, an antibody block- ing interleukin 6 (IL-6) receptor. Further information about Conventional B-ALL therapy is composed of intensive, multi- the efficacy, challenges and ways to address obstacles to agent chemotherapy delivered in several cycles of treat- CAR-T cell therapy can be found in [16, 17]. ment over 2–3 years, and is associated with numerous side effects and long-term consequences [5]. Naked monoclonal Immunotherapy targets antibodies (mAbs), such as rituximab, can be added to the chemotherapy of a subset of adult B-ALL patients at the What makes a good target induction phase, due to their low price, broad availability for cancer immunotherapy? and mild side effects. Other, more advanced, immunothera- An ideal target for cancer immunotherapy should be pies such as BiTe and CAR-T cells play an important role in expressed exclusively on malignant cells and should be the treatment of R/R B-ALL patients, as a bridge therapy essential for cancer cell proliferation and survival. How- to allogeneic hematopoietic stem cell transplantation (allo- ever, none of the targets currently in use meets these -HSCT). Some attempts are also being made to apply CAR-T stringent criteria. The vast majority of antigens utilized in cells to treat relapse after allo-HSCT [10]. the immunotherapy of B-ALL are B cell-specific proteins Currently available immunotherapy options in the treat- that occur both in malignant and normal B cells, but are ment of B-ALL are extensively described in [11]. Briefly, the rarely present in other tissues. This usually ensures suf- vast majority of registered immunotherapies target surface ficient efficacy and safety of the targeted immunotherapy. antigens specific for B cells, namely CD19, CD20, CD22, The resulting on-target off-tumor toxicity to normal B cells with mAbs recognizing these antigens. Apart from naked is an unavoidable but manageable side effect. However, mAbs that work mainly through the induction of host’s ef- B-ALL subtypes derived from early stages of B cell develop- fector cell-dependent mechanisms (immunophagocytosis, ment, with more stem cell-like features such as MLLr- or antibody-dependent cytotoxicity), mAb derivatives such as TCF3-ZNF384 fusion-B-ALL, in response to CD19-directed antibody-drug-conjugates (ADC) or BiTE are also used in immunotherapies were shown to undergo lymphoid-to- clinical practice [12]. Additionally, cellular therapy using -myeloid lineage switch [7, 8, 18]. This resulted in the loss autologous, patient-derived T cells genetically modified with of B cell phenotype and precluded further immunotherapy chimeric antigen receptors (CARs) has been available since targeting, not only CD19 but also other B cell-specific 2017 [13]. CARs are synthetic constructs composed of sev- antigens. eral domains: 1) an extracellular domain responsible for Stability, sustainability, and abundance of a target an- the recognition of tumor-specific targets, which is derived tigen in all leukemic clones are other important features. from mAb; 2) a transmembrane part; and 3) intracellular Indeed, the outcome of immunotherapy usually corre- domains responsible for the transmission of activating sig- lates with high antigen density on malignant cells [1, 19]. nals and co-stimulation,