Abstract: Chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has revolutionized the treatment landscape for patients with relapsed or refractory (R/R) B-cell malignancies. However, the emergence of relapse with CD19-negative tumors presents a significant challenge, necessitating the exploration of alternative therapeutic targets. CD22 has emerged as a promising candidate due to its consistent expression in malignant B cells, offering a complementary approach to CD19-targeted therapies. This review provides a comprehensive examination of the methodology, detailed results, clinical implications, and future perspectives regarding CD22-targeted therapies in B-cell hematologic malignancies. Methodologically, an extensive literature search was conducted to synthesize findings from preclinical investigations and clinical trials, examining the molecular and physiological characteristics of the CD22 antigen and the development and clinical application of CD22-targeted therapies. Results from pivotal clinical trials, notably with Inotuzumab ozogamicin and Moxetumomab pasudotox-tdfk, demonstrate promising efficacy and manageable safety profiles. However, treatment failures and disease relapses underscore the need for continued research to elucidate resistance mechanisms and optimize treatment strategies.Introduction: The introduction of chimeric antigen receptor (CAR)-T cell therapy targeting CD19 has undeniably transformed the treatment landscape for patients with relapsed or refractory (R/R) B-cell malignancies. However, a persistent challenge in this therapeutic paradigm is the emergence of relapse with CD19-negative tumors, highlighting the urgent need for alternative therapeutic targets. CD22 has emerged as a promising candidate due to its consistent expression in malignant B cells, offering a complementary approach to CD19-targeted therapies. This review aims to provide a thorough examination of the methodology, detailed results, clinical implications, and future directions regarding CD22-targeted therapies in B-cell hematologic malignancies.
Methods: This review comprehensively synthesizes findings from a range of studies, including preclinical investigations and clinical trials, to elucidate the landscape of CD22-targeted therapies. Methodologically, an extensive literature search was conducted utilizing databases such as PubMed, Embase, and Scopus, employing keywords related to CD22, B-cell hematologic malignancies, CAR-T cell therapy, and antibody-drug conjugates (ADCs). Studies examining the molecular and physiological characteristics of the CD22 antigen, as well as the development and clinical application of CD22-targeted therapies, were meticulously analyzed. Primary investigations, including pivotal clinical trials and preclinical studies, were critically evaluated to assess the efficacy, safety profile, and therapeutic potential of CD22-targeted agents, with a focus on ADCs such as Inotuzumab ozogamicin and Moxetumomab pasudotox-tdfk.
Results: The results of this comprehensive review underscore the promising efficacy and manageable safety profile of CD22-targeted therapies in the treatment of B-cell hematologic malignancies. Notably, clinical trials evaluating Inotuzumab ozogamicin have demonstrated encouraging outcomes, with a significant proportion of patients achieving complete responses and sustained remissions. For instance, in a subset of 90 R/R B-ALL patients, Inotuzumab ozogamicin exhibited a notable complete response rate of 58%, with a median remission duration of 7 months. Similarly, Moxetumomab pasudotox-tdfk has shown promising responses in patients with relapsed or refractory hairy-cell leukemia, further emphasizing the broad therapeutic potential of CD22-targeted therapies. However, treatment failures and instances of disease relapse have also been observed, underscoring the need for continued research to elucidate mechanisms of resistance and optimize treatment strategies.
Discussion: The expression of CD22 on malignant B cells represents a significant therapeutic opportunity for patients with B-cell hematologic malignancies, particularly those who have relapsed following CD19-targeted therapies. With CD22 prevalence in over 90% of B-ALL cases and its consistent expression across various B-cell malignancies, targeting this antigen holds great promise in expanding therapeutic options. Advancements in CD22-targeted therapies, including the development of second-generation ADCs and combination regimens, offer avenues for overcoming resistance mechanisms and improving treatment outcomes. Moreover, ongoing research focused on understanding the structural and functional characteristics of CD22 is essential for optimizing therapeutic strategies and designing tailored interventions. Future directions may include exploring novel combination therapies, investigating mechanisms of resistance, and developing innovative strategies to enhance the efficacy of CD22-targeted therapies.
Conclusions: In conclusion, CD22-targeted therapies emerge as a promising therapeutic approach for the management of B-cell hematologic malignancies, particularly for patients with CD19 CAR-T resistant disease. This comprehensive review highlights the methodological approaches, detailed results, clinical implications, and future perspectives regarding CD22-targeted therapies, underscoring their potential to address unmet medical needs in this patient population. Continued research and innovation in this field are crucial to further elucidate the therapeutic potential of CD22-targeted agents and ultimately improve outcomes for patients with B-cell hematologic malignancies.
Authors contribution: The authors of this review, led by Heng Mei (HM) and Chenggong Li (CL) from the prestigious Hubei Clinical Medical Center of Cell Therapy for Neoplastic Disease and the Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, bring together expertise in hematology, oncology, and translational research. Jia Xu (JX) and Wenjing Luo (WL) contributed significantly to the writing and analysis of the manuscript, with WL conducting subgroup analysis of clinical data and both JX and WL responsible for designing figures and summarizing tables. Their collaborative efforts, supported by grants from various foundations, reflect a commitment to advancing knowledge in the field and improving treatment strategies for B-cell hematologic malignancies.
