CD20-Targeted T Cells after Stem Cell Transplantation for High Risk and Refractory Non-Hodgkin's Lymphoma Lawrence G. Lum, Archana Thakur, Qin Liu, Abhinav.

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CD20-Targeted T Cells after Stem Cell Transplantation for High Risk and Refractory Non-Hodgkin's Lymphoma Lawrence G. Lum, Archana Thakur, Qin Liu, Abhinav Deol, Zaid Al-Kadhimi, Lois Ayash, Muneer H. Abidi, Cassara Pray, Elyse N. Tomaszewski, Patricia A. Steele, Dana L. Schalk, Hiroshi Yano, Alice Mitchell, Melissa Dufresne, Joseph P. Uberti, Voravit Ratanatharathorn Biology of Blood and Marrow Transplantation Volume 19, Issue 6, Pages 925-933 (June 2013) DOI: 10.1016/j.bbmt.2013.03.010 Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 1 (A) Treatment schema. The chemotherapy preparative regimen involved BEAM, which consisted of carmustine 300 mg/m2 × 1 dose at day −7, etoposide at 100 mg/m2 every 12 hours and cytarabine 100 mg/m2 every 12 hours on days −6 through −3, and melphalan 140 mg/m2 × 1 dose at day −2, day of rest on day −1, and transplantation on day 0. (B) Process of heteroconjugation of anti-CD3 with rituximab. Step 1 shows cross-linking of Traut’s reagent to anti-CD3 (OKT3) mAb and the cross-linking of Sulpho-SMCC to anti-CD20 (rituximab); step 2 shows the heteroconjugation of the cross-linked anti-CD3 with the cross-linked rituximab; and step 3 shows formation of anti-CD3 × anti-CD20 BiAb (CD20Bi). (C) SDS-PAGE gel of the parent monoclonal antibodies and the heteroconjugated CD20Bi. Lane 1: Protein ladder; lane 2: anti-CD20 mAb; lane 3: anti-CD3 mAb; lane 4: CD20Bi. (D) The schema shows T cell expansion after leukapheresis of the patient, harvesting, and arming of ATC with CD20Bi, cryopreservation in aliquots for infusions after SCT at the designated time points for the treatment schema shown in A. Biology of Blood and Marrow Transplantation 2013 19, 925-933DOI: (10.1016/j.bbmt.2013.03.010) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 2 Engraftment. (A) Daily mean absolute white blood cell count, lymphocyte, absolute neutrophil, and monocyte counts for 12 patients. (B) Flow cytometry performed on PBMCs from patients at the indicated time points after SCT shows mean proportions of CD3+, CD4+, and CD8+ T cells after SCT. (C) Overall survival of 12 patients transplanted for NHL. The Kaplan-Meier curve is presented for the entire population (All patients), the subgroup of patients who underwent transplantation in remission (REM), and the subgroup of patients who were transplantation in partial remission or had refractory disease (PR + Ref). Biology of Blood and Marrow Transplantation 2013 19, 925-933DOI: (10.1016/j.bbmt.2013.03.010) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 3 (A) Cytotoxicity directed at DAUDI (left) and K562 (right). Fresh PBMCs from patient who received aATC were tested in 51Cr release cytotoxicity assay 2 weeks to 3 months post-SCT. (B) IFN-γ EliSpots against DAUDI (left) and K562 (right) in patients who received aATC and SCT (SCT + IT) and patients who received SCT alone (SCT alone). Fresh PBMCs for patients who received aATC and SCT that were plated onto DAUDI and K562 targets (right two columns in each panel). Fresh PBMCs for patients who received SCT alone were plated onto DAUDI and K562 targets (left two columns in each panel). Biology of Blood and Marrow Transplantation 2013 19, 925-933DOI: (10.1016/j.bbmt.2013.03.010) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions

Figure 4 Changes in serum cytokines and chemokines. (A) Infusions of aATC-induced cytokines and chemokines. aATC infusions enhanced cytokines IL-2R and IL-12 and IFN-γ–induced chemokines CXCL10 (IP-10) and CXCL9 (MIG) in 4 patients at indicated time points (∗P < .05). (B) Top: sequential mean (±SD) fold increase in serum levels for T cell proliferation inducing cytokines IL-2, IL-7, and IL-15 (left) and serum chemokines MIP-1β and MIP-1α and IFN-γ–induced chemokines CXCL10 (IP-10) and CXCL9 (MIG). Bottom: sequential serum levels for IFN-γ and IL-12. Serum samples were analyzed in 3 patients after the second infusion at the designated times. (C) Transfer and reconstitution of IgG and anti-TT. The results for individual patients are presented. Total IgG was tested before and at 3 months after SCT to determine the levels of IgG transferred in the stem cell product. aATC infusions did not affect total IgG levels in the serum. (D) Anti-TT before and at 3 months after SCT were analyzed to determine whether the levels of specific anti-TT transferred in the stem cell product. Biology of Blood and Marrow Transplantation 2013 19, 925-933DOI: (10.1016/j.bbmt.2013.03.010) Copyright © 2013 American Society for Blood and Marrow Transplantation Terms and Conditions