Systematic Review and Meta-Analysis of CAR T-Cells Targeting CD22 in Relapsed/Refractory B-Cell Malignancies Komal Adeel1, Nathan Fergusson2,3, Harold Atkins3,4, and Kevin A Hay1,5,6 1Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada; 2Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada; 3Ottawa Hospital Research Institute, Ottawa, ON, Canada, 4The Ottawa Hospital General Campus, BMT, Ottawa, ON, Canada; 5Terry Fox Laboratory, BC Cancer Research Institute, Vancouver, BC, Canada; 6L/BMT Program of BC, Vancouver, BC, Canada

INTRODUCTION RESULTS DISCUSSION

• Chimeric antigen (CAR) T-cell therapies have shown promising CAR T-cell therapy solely targeting CD22 had an estimated best CR of 66% [95% CI, 52-79%] in ALL patients (n= 100) (Figure 1), many of whom had • Early phase trials of CD22 CAR T-cells have shown high efficacy in treating relapsed/refractory (R/R) B-cell malignancies, with previously relapsed following CD19 CAR T-cell therapy. CAR T-cell therapies targeting both CD19 and CD22 used a variety of dual-targeting methods, and remission rates in R/R B-ALL, including in patients who CD19 being the most well-established CAR T-cell target. together had an estimated best CR rate of 95% [95% CI, 87-99%] in ALL patients (n= 150) and 51% [95% CI, 38-63%] in NHL patients (n= 81). previously failed CD19 CAR T-cell therapy.

• CAR T-cells targeting CD22 offer a novel treatment option for patients The estimated incidence of total and severe (grade ≥3) release syndrome (CRS) were 86% [95% CI, 80-92] and 3% [95% CI, 1-8%] (Figure 2). • CD19/CD22 CAR-T cells have shown high remission rates with R/R B-cell malignancies, particularly those that fail or relapse after Estimated incidence of neurotoxicity and severe neurotoxicity were 14% [95% CI, 8-22%] and 1% [95% CI, 0-3%], respectively (Figure 3). Comparing in R/R B-ALL and substantial remission rates in R/R B-NHL. CD19 CAR T-cell therapy. CD22 and CD19/CD22 trials, we did not see a significant difference in incidence of CRS (p = 0.93) or neurotoxicity (p = 0.18) between the two groups. • There is no indication that CD19/CD22 dual-target CAR T- • Targeting CD19 and CD22 simultaneously may prevent antigen-negative Among studies that reported 30-day mortality, the total incidence was 3% (8/250). Reporting of long-term survival outcomes was limited. cell therapies have greater risk of adverse events relapse, a major issue observed in CD19 CAR T-cell trials [1]. However, compared to single-target CD22 therapy. dual-targeting may result in greater toxicity. • Compared to CD19 CAR T-cell meta-analyses, both CD22 OBJECTIVE: We conducted a systematic review to evaluate the efficacy and and CD19/CD22 CAR T-cells have lower rates of severe toxicity of CD22 CAR T-cells, alone or in combination with other antigen CRS and neurotoxicity [2] but higher rates of total CRS [3]. targets, in treating R/R B-cell malignancies. • While our results suggest that dual targeting may have increased efficacy compared to single-target therapy, METHODS variability in CAR construct, dose, and patient factors between clinical trials limits comparisons. Data sources: MEDLINE, EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials (inception to July 8, 2020). • Trials directly comparing dual vs. single-target CAR T-cell therapies, and comparing various methods of dual Study selection criteria: We included reports of clinical trials investigating targeting, are needed to establish the most effective CD22-targeting CAR T-cells in B-cell malignancies (ALL, NHL, CLL) that approach. reported complete response (CR). Full-length articles and conference abstracts were included in meta-analysis.

Data extraction: Data items extracted include best CR (defined as CONCLUSION proportion of patients achieving CR at any point during follow-up), adverse events, and survival data. Data was extracted by duplicate reviewers. Early phase clinical trials of CD22 and CD19/CD22 CAR T- cells demonstrate efficacy and minimal severe adverse Statistical analysis: A random effects model using the DerSimonian and events. Long-term data is needed to determine survival Laird method of arcsine transformed proportion was used to pool outcome proportions. Meta-regression was performed for subgroup analysis. outcomes.

INCLUDED STUDIES Acknowledgements

This project was funded in part by a 14 early phase (I-II) clinical trial studies included (total 331 patients) grant from BioCanRx (FY20/ES15). à We also thank Risa Shorr, MLS, for 3 CD22 CAR T-cell studies, all in ALL patients peer review of the search strategy à 11 CD19/CD22 CAR T-cell studies: 7 in ALL patients, 3 in NHL used in this review. patients, and 1 including both ALL and NHL patients References

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2. Anagnostou T, Riaz IB, Hashmi SK, Murad MH, Kenderian SS. Anti-CD19 chimeric antigen receptor T-cell therapy in acute lymphocytic leukaemia: a systematic review and meta-analysis. Lancet Haematol. 2020 Nov;7(11):e816- e826. doi: 10.1016/S2352-3026(20)30277-5. PMID: 33091355.

3. Grigor EJM, Fergusson D, Kekre N, et al. Risks and Benefits of Chimeric Antigen Receptor T-Cell (CAR-T) Therapy in Cancer: A Systematic Review and Meta- Analysis. Transfus Med Rev. 2019;33(2):98-110. doi:10.1016/j.tmrv.2019.01.005

Contact information

Corresponding author: Kevin A. Hay [email protected]