CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

Lanza, Francesco; Madon, E; Rondoni, Michela; Massari, Evita; Faini, Angelo Corso; Malavasi, Fabio

doi:10.3390/cancers12020303

Cited by 49 publications

(40 citation statements)

References 52 publications

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“…The experience and the clinical success obtained with anti-CD20 mAbs revitalized the interest in this strategy [ 3 ]. Similar strategies were applied for therapeutic targeting of CD22 [ 4 ]. Utilizing multiple myeloma (MM) as a tumor model, a first limitation is represented by the fact that plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells.…”

Section: Premisementioning

confidence: 99%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

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Monoclonal antibodies (mAbs) were initially considered as a possible “magic bullet” for in vivo elimination of tumor cells. mAbs represented the first step: however, as they were murine in nature (the earliest experience on the field), they were considered unfit for human applications. This prompted the development of techniques for cloning the variable regions of conventional murine antibodies, genetically mounted on human IgG. The last step in this years-long process was the design for the preparation of fully human reagents. The choice of the target molecule was also problematic, since cancer-specific targets are quite limited in number. To overcome this obstacle in the planning phases of antibody-mediated therapy, attention was focused on a set of normal molecules, whose quantitative distribution may balance a tissue-dependent generalized expression. The results and clinical success obtained with anti-CD20 mAbs revived interest in this type of strategy. Using multiple myeloma (MM) as a tumor model was challenging first of all because the plasma cells and their neoplastic counterpart eluded the efforts of the Workshop on Differentiation Antigens to find a target molecule exclusively expressed by these cells. For this reason, attention was turned to surface molecules which fulfill the requisites of being reasonably good targets, even if not specifically restricted to tumor cells. In 2009, we proposed CD38 as a MM target in virtue of its expression: it is absent on early hematological progenitors, has variable but generalized limited expression by normal cells, but is extremely high in plasma cells and in myeloma. Further, regulation of its expression appeared to be dependent on a variety of factors, including exposure to all-trans retinoic acid (ATRA), a potent and highly specific inducer of CD38 expression in human promyelocytic leukemia cells that are now approved for in vivo use. This review discusses the history of human CD38, from its initial characterization to its targeting in antibody-mediated therapy of human myeloma.

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Section: Premisementioning

confidence: 99%

The Circular Life of Human CD38: From Basic Science to Clinics and Back

et al. 2020

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“…However, at later time points the mAb was sorted and colocalized with late endosomes/lysosomes. G544, the mAb portion of InO, targets epitope A, which is located at the N-terminal domain and is also thought to promote crosslinking [87]. Fingrut et al, recently presented a case of a patient with low CD22 expression on leukemic blasts (<30% of normal levels) that showed a very good response and survival benefit from InO treatment [96].…”

Section: Adc/ab-cd22 Endocytosismentioning

confidence: 99%

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

2021

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Biologically-based therapies increasingly rely on the endocytic cycle of internalization and exocytosis of target receptors for cancer therapies. However, receptor trafficking pathways (endosomal sorting (recycling, lysosome localization) and lateral membrane movement) are often dysfunctional in cancer. Antibody-drug conjugates (ADCs) have revitalized the concept of targeted chemotherapy by coupling inhibitory antibodies to cytotoxic payloads. Significant advances in ADC technology and format, and target biology have hastened the FDA approval of nine ADCs (four since 2019). Although the links between aberrant endocytic machinery and cancer are emerging, the impact of dysregulated internalization processes of ADC targets and response rates or resistance have not been well studied. This is despite the reliance on ADC uptake and trafficking to lysosomes for linker cleavage and payload release. In this review, we describe what is known about all the target antigens for the currently approved ADCs. Specifically, internalization efficiency and relevant intracellular sorting activities are described for each receptor under normal processes, and when complexed to an ADC. In addition, we discuss aberrant endocytic processes that have been directly linked to preclinical ADC resistance mechanisms. The implications of endocytosis in regard to therapeutic effectiveness in the clinic are also described. Unexpectedly, information on endocytosis is scarce (absent for two receptors). Moreover, much of what is known about endocytosis is not in the context of receptor-ADC/antibody complexes. This review provides a deeper understanding of the pertinent principles of receptor endocytosis for the currently approved ADCs.

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“…The methods and materials used for this procedure will follow the protocol reported by Weigert et al [12] B-ALL cells will be obtained from a relapsed 18-24 year old patient and engrafted into mice via tail-vein injections without prior irradiation [12]. Tumor growth will be assessed through in vivo antibody fluorescent imaging, with anti-CD22 as the fluorescent antibody [13]. Once the bone marrow blasts of the entire cohort exceed 30%, the mice will be considered leukemic [12] and the experiment will begin.…”

Section: Establishment Of B-all Patient-derived Xenograftsmentioning

confidence: 99%

“…Tumor shrinkage will be assessed weekly through in vivo antibody fluorescent imaging using anti-CD22 antibodies [13]. Moribund mice will be euthanized as per standard protocol [10].…”

Section: Experimental Designmentioning

confidence: 99%

Efficacy of CRISPR-Cas9 CAR T-Cell Therapy vs. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia

2021

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Introduction: With immunotherapy drugs such as Blinatumomab (Blincyto), the current overall survival rate of relapsed/refractory B Lymphocyte Acute Lymphoblastic Leukemia (B-ALL) is 7.8 months in adults. However, with CRISPR-Cas9 gene editing, CAR T-cell therapy may extend survival. By knocking out T-cell receptors (TCRs) and HLA class I receptors on T-cells, CRISPR-Cas9 edited CAR T-cells could become a universal treatment alternative for B-ALL. This study compares the efficacy of CRISPR-Cas9 edited CAR T-cell therapy, a new era of CAR T-cell therapy, to the treatment of relapsed/ refractory B-ALL with Blinatumomab in mice.Methods: A cohort of 30 NSG mice receiving xenografts from an 18-24 year old patient with relapsed B-ALL will be randomly assigned to one of three groups, where they will receive treatment with: (1) mock transduced T-cells, (2) Blincyto, or (3) CRISPR-Cas9 edited TRAC-and B2M-knockout CAR T-cells. Another cohort of 30 NSG mice, receiving human skin xenografts from a healthy donor, will also be assigned to one of the groups and treated accordingly. Tumour shrinkage will be analyzed through in vivo antibody fluorescent imaging in the first cohort. Graft Vs Host Disease (GvHD) development will be assessed in the second cohort. Results: It is expected that mice treated with CRISPR-Cas9 edited CAR T-cells will be more effective at eliminating tumours. Compared to mice treated with Blincyto or mock-transfused T-cells, these mice will exhibit the highest overall response rates, complete response rates and tumour shrinkage rates, and the lowest relapse rates. It is also expected that these mice will not develop GvHD. Discussion: The use of CRISPR-Cas9 edited CAR T-cells in the treatment of B-ALL reveals a new facet to cancer therapeutics. The efficacy of this treatment will be demonstrated through greater tumour shrinkage rates and higher overall response rates than treatment with Blincyto, the current standard treatment drug for B-ALL. Conclusion: Current treatments involving Blinatumomab or conventional CAR T-cell therapy are expensive and therefore inaccessible to many. These results could demonstrate that CRISPR-Cas9 edited CAR T-cell therapy is viable as a safe, universal and more affordable alternative for relapsed/refractory B-ALL treatment.

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CD22 Expression in B-Cell Acute Lymphoblastic Leukemia: Biological Significance and Implications for Inotuzumab Therapy in Adults

Cited by 49 publications

References 52 publications

The Circular Life of Human CD38: From Basic Science to Clinics and Back

The Circular Life of Human CD38: From Basic Science to Clinics and Back

Impact of Endocytosis Mechanisms for the Receptors Targeted by the Currently Approved Antibody-Drug Conjugates (ADCs)—A Necessity for Future ADC Research and Development

Efficacy of CRISPR-Cas9 CAR T-Cell Therapy vs. Blinatumomab in the Treatment of Acute Lymphoblastic Leukemia

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