The Humanized Anti PD-1 Antibody, CT-011, Increases Specific CD4+ Effector/Memory and Memory T Lymphocytes in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Following Autologous Stem Cell Transplantation (AuSCT).
Authors: Rotem-Yehudar Rinat , Armand Philippe , Devine Steve , Fay Joseph W. , Hosing Chitra , Mapara Markus Y , Campagnero Erica , Uberti Joseph P. , Avigan David , Ballen Karen K , Winter Jane N. , Nagler Arnon , Gordon Leo I. 
Published: October 2019

Abstract
Abstract 1216
Poster Board I-238

Background:
PD-1 (Program Death-1), an immune inhibitory receptor and its ligands PD-L1 and PD-L2, participate in peripheral tolerance and play a key role in immune suppression and evasion mechanisms in cancer and chronic infectious diseases. PD-1 inhibits activation signals and functions as a pro-apoptotic receptor in effector lymphocytes, and consequently regulates the extent and duration of specific adaptive and innate immune responses. CT-011, a humanized antibody, blocks the function of PD-1, resulting in increased activities of T and NK cells in vitro and in enhanced tumor immunity in experimental tumor models. At the molecular level, the antibody enhances PI3K-mediated survival and trafficking signals, attenuates cell death in effector/memory (CD4+CD45RO+) cells, and enhances trafficking in response to Stromal Cell-derived Factor-1 (SDF-1). We hypothesized that CT-011 would enhance effector/memory cells in patients with DLBCL after AuSCT and delay recurrence.

Methods:
We treated 41 patients (pts) with DLBCL from 30-90 days after AuSCT with CT-011 and now report data on effector/memory and memory lymphocytes in the first 30 pts. CT-011 was given at a dose of 1.5mg/kg for 3 doses, 6 weeks apart. The primary endpoint was to determine the proportion of patients who have not relapsed or died within 18 months following autologous PBSCT, and it is too early for that analysis. Our secondary endpoint was to measure the number of effector /memory and memory lymphocytes before and after treatment, and those data are the subject of this report.

Results:
Flow cytometry analyses (Table) on pre (baseline: BL) and post-treatment blood samples from the first 30 pts enrolled show elevated levels of specific effector/memory and memory CD4+ T lymphocytes following treatment with CT-011; the median absolute number (ABS) of effector/memory CD4+CD45RO+CD62L-CCR7- cells was increased by +49% from BL (p<0.05) 6 weeks following the first treatment with CT-011, reaching a 2 fold increase in the ABS levels from BL and a 45% increase in the median percentage of the total lymphocyte population (p<0.05) 4 weeks after the third antibody treatment (week 16). The percentage of peripheral memory CD4+ CD62L-CD127+ cells was also increased by 61% from BL (median, p<0.05) on week 16.
The observed increase, particularly of the effector/memory CD4+CD45RO+CD62L-CCR7- lymphocytes, a subset directly linked to PD-1 activity and to tumor immune surveillance, likely indicates a specific cellular response to CT-011, since no significant changes were observed for other memory cell subsets including CD4+CD45RO+CD62L+CCR7+cells, CD4+ CD62L+CD127+ cells, CD8+ CD62L-CD127+, CD8+CD62L+CD127+ cells or CD4+CD25+ FOXP3+ suppressor T cells. Overall no changes were observed in the level of total lymphocytes or T cells throughout 16 weeks of follow up from the 1st antibody treatment. Transient reduction of 32% (median, p<0.05) and 25% (median, p<0.05) in the ABS levels of CD3+CD8+ and CD3+CD45RO+, respectively, was observed at week 12, which recovered to baseline or higher levels on week 16. These changes may be explained by trafficking or recycling of CD8+ effector/memory cells from the periphery to target organs.

Conclusions:
Consistent with its mechanism of action, CT-011 increases the levels of specific CD4+ effector/memory and memory T lymphocytes. This is the first demonstration of safe induction of effector memory and memory lymphocytes, essential components of tumor- immune control, in lymphoma patients following AuSCT. This antibody may have promise for the treatment of lymphoma.

Disclosures:
Rotem-Yehudar: Cure Tech: Employment. Gordon:Cure Tech: Membership on an entity's Board of Directors or advisory committees.