Targeting CD138−/CD20+ Clonogenic Myeloma Precursor Cells Decreases These Cells and Induces Transferable Antimyeloma Immunity Lawrence G. Lum, Archana.

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Targeting CD138−/CD20+ Clonogenic Myeloma Precursor Cells Decreases These Cells and Induces Transferable Antimyeloma Immunity Lawrence G. Lum, Archana Thakur, Sri Vidya Kondadasula, Zaid Al-Kadhimi, Abhinav Deol, Elyse N. Tomaszewski, Hiroshi Yano, Dana L. Schalk, Lois Ayash, Jeffrey A. Zonder, Joseph P. Uberti, Muneer H. Abidi, Voravit Ratanatharathorn Biology of Blood and Marrow Transplantation Volume 22, Issue 5, Pages 869-878 (May 2016) DOI: 10.1016/j.bbmt.2015.12.030 Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 (A) Treatment schema showing leukapheresis to obtain T cells for expansion, followed by baseline bone marrow biopsy and phenotyping. After expansion ex vivo and arming of ATCs from the patients, 10 × 109 BATs were infused on 2 occasions 1 week apart, followed by a second biopsy to evaluate changes in the BM. Immune testing was performed as indicated at the various time points after SCT. Four patients received BATs booster infusions. (B) (Upper) Daily lymphocyte (Lymph) and ANC counts in 12 patients. (Lower) Daily mean platelet counts. (C) (Upper, Left) CMPC population at 2 weeks post-BATs compared with pre-BATs in all 12 patients. (Upper, Right) Waterfall chart of percent change in CMPC population at 2 weeks post-BATs compared with pre-BATs in patients who remained in remission (uCR) and those who relapsed (REL). (Lower) Absolute percent positive CMPC population in patients who remained in remission (uCR) and those who relapsed (REL). Biology of Blood and Marrow Transplantation 2016 22, 869-878DOI: (10.1016/j.bbmt.2015.12.030) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 (A) Cytotoxicity and IFN-γ ELISPOTs directed at RPMI 8226, Daudi, and K562 targets after BATs infusions (Upper) and after SCT (Lower) in 12 patients. (B) (Left and Middle) IFN-γ ELISPOTs in patients who received BATs + SCT compared with patients who received SCT only (control group). (Right) The fold increase in IFN-γ ELISPOTs against RPMI 8226 at 6 to 12 months post-SCT in patients who remained in remission (uCR) compared with patients who relapsed (REL). (C) Data for 4 patients who received a single “booster” infusion of BATs at 6 to 15 months post-SCT. Booster infusion of BATs induced increases in IFN-γ ELISPOT responses when stimulated with MM-specific targets (RPMI 8226) and NK targets (K562) in all 4 patients at 2 and 4 weeks after booster BATs infusions. Biology of Blood and Marrow Transplantation 2016 22, 869-878DOI: (10.1016/j.bbmt.2015.12.030) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 (A) Cytotoxicity and IFN-γ ELISPOTs directed at RPMI 8226, Daudi, and K562 targets after BATs infusions (Upper) and after SCT (Lower) in 12 patients. (B) (Left and Middle) IFN-γ ELISPOTs in patients who received BATs + SCT compared with patients who received SCT only (control group). (Right) The fold increase in IFN-γ ELISPOTs against RPMI 8226 at 6 to 12 months post-SCT in patients who remained in remission (uCR) compared with patients who relapsed (REL). (C) Data for 4 patients who received a single “booster” infusion of BATs at 6 to 15 months post-SCT. Booster infusion of BATs induced increases in IFN-γ ELISPOT responses when stimulated with MM-specific targets (RPMI 8226) and NK targets (K562) in all 4 patients at 2 and 4 weeks after booster BATs infusions. Biology of Blood and Marrow Transplantation 2016 22, 869-878DOI: (10.1016/j.bbmt.2015.12.030) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 Transfer and reconstitution of anti-SOX2 IgG. The results for individual patients are presented. (A) (Right) Anti-SOX2 IgG antibodies in all 12 patients at pre-BATs, post-BATs, and 1 month and 3 months post-SCT. (Left) Control autologous SCT patients who did not receive BATs showed no difference in serum anti-SOX2 antibody levels between pre-SCT and 1 month post-SCT or pre-SCT and 3 months post-SCT. (B) Shows the boxplots of the serum anti-SOX2 titers of those who are in uCR and those who progressed (REL), they are nearly nonoverlapping. Biology of Blood and Marrow Transplantation 2016 22, 869-878DOI: (10.1016/j.bbmt.2015.12.030) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Serum cytokine and chemokine profiles. Analysis of sequential serum samples after BATs infusions and after SCT show increased IL-2R and IL-12 levels at 1 to 3 months post-SCT. IL-2 and TNF-α levels increased post-BATs, but not post-SCT, whereas chemokines CXCL9 (MIG) and CXCL10 (IP-10) increased at 1 month post- SCT. Biology of Blood and Marrow Transplantation 2016 22, 869-878DOI: (10.1016/j.bbmt.2015.12.030) Copyright © 2016 American Society for Blood and Marrow Transplantation Terms and Conditions