CC-122 Expands Activated and Memory CD4 and CD8 T Cells In Vivo and Induces T Cell Activation Ex Vivo in Subjects with Relapsed or Refractory Diffuse Large B Cell Lymphoma and Multiple Myeloma

Abstract

Background: CC-122 is a first in class PPMTM pleiotropic pathway modifier compound with multiple biological activities including potent anti-proliferative activity against B lineage cells, anti-angiogenic activity and immunomodulatory effects. CC-122 binds cereblon, and promotes ubiquitination of lymphoid transcription factors Ikaros and Aiolos, leading to their subsequent degradation resulting in activation of T cells. The immunological properties of CC-122 including effects on T cell subset number in vivo and T cell cytokine production ex vivo was explored in subjects with advanced aggressive non-Hodgkin Lymphoma (NHL) and Multiple Myeloma (MM) enrolled in a Phase 1b trial (NCT01421524) at 3 mg QD and 4 and 5 mg 5/7 days dosed in 28 day cycles until disease progression. Methods: As of June 25, 2015, 76 total DLBCL and MM subjects were enrolled in the expansion phase of the study. Assessments for T cell subset numbers were performed at screening (baseline), cycle 1 day 15 (C1D15), cycle 1 day 22, cycle 2 day 15 and cycle 2 day 22 by flow cytometric immunophenotyping of fresh whole blood. Ex vivo whole blood T cell activation as measured by IL-2, IL-6, IFNg and GM-CSF cytokine production was performed using the anti-CD3 TruCulture Assay. Changes from baseline were evaluated using the t test with p<0.05 considered significant. Results: T cell subsets which were significantly changed are shown in italics in Table 1. In MM subjects (n=19-21) and DLBCL subjects (n=30-31), CC-122 treatment significantly expanded several T cell activator and memory T cell subsets while decreasing naïve T cells. A single dose of CC-122 on C1D1 activated T cells as measured in an ex vivo T cell activation assay in MM subjects (n=6-13) and DLBCL subjects (n=5-12) (Table 2). In addition, we evaluated potential correlations of clinical outcome with baseline biomarker and biomarker changes upon CC-122 treatment. Table 1. MM n=19-21 NHL n=30-31 T cell Parameter Phenotype Baseline cells/mm3 Median % Change at C1D15 from Baseline P Baseline cells/mm3 Median % Change at C1D15 from Baseline P Total T cells ABS CD3+ 636.9 17.733 0.24747 522.94 43.83 0.03638 Total T helper ABS CD3+/CD4+/CD8- 275.38 18.333 0.07812 238.96 13.428 0.09893 T helper Activated ABS CD3+/CD4+/CD8-/HLA-DR+ 62.34 105.769 0.00238 57.11 78.571 0.01567 T helper Total Naïve ABS CD3+/CD4+/CD8-/45RA+/45RO- 69.07 -54.545 0.0038 47.94 -47.841 0.03159 T helper Effector CD62L+ ABS CD3+/CD4+/CD8-/45RA+/62L+ 117.62 0 0.16621 93.74 -6 0.14611 T helper Effector CD62L- ABS CD3+/CD4+/CD8-/45RA+/62L- 21.38 -25.862 0.15196 28.44 -20.161 0.08548 T helper Total Memory ABS CD3+/CD4+/CD8-/45RA-/45RO+ 137.93 41.176 0.05373 119.15 36 0.01915 T helper Central Memory ABS CD3+/CD4+/CD8-/45RA-/62L+ 91.9 47.451 0.01953 75.74 37.143 0.01275 T helper Effector Memory ABS CD3+/CD4+/CD8-/45RA-/62L- 44.17 18.147 0.17768 41.07 19.375 0.04749 Total T cytotoxic ABS CD3+/CD4-/CD8+ 334.07 18.044 0.27499 265.7 43.823 0.0127 T cytotoxic Activated ABS CD3+/CD4-/CD8+ /HLA-DR+ 176.76 100 0.20781 121.3 96.454 0.00686 T cytotoxic Total Naïve ABS CD3+/CD4-/CD8+ /45RA+/45RO- 173.69 -35.714 0.15126 116.04 -32.667 0.89774 T cytotoxic Effector CD62L+ ABS CD3+/CD4-/CD8+ /45RA+/62L+ 127.28 20.727 0.24151 93.43 17.419 0.09599 T cytotoxic Effector CD62L- ABS CD3+/CD4-/CD8+ /45RA+/62L- 151.72 -14.286 0.28394 120.98 -18.301 0.18068 T cytotoxic Total Memory ABS CD3+/CD4-/CD8+ /45RA-/45RO+ 55.03 167.402 0.26292 54.13 184.615 0.01034 T cytotoxic Central Memory ABS CD3+/CD4-/CD8+ /45RA-/62L+ 26.83 160.417 0.00013 18.78 264.087 0.00169 T cytotoxic Effector Memory ABS CD3+/CD4-/CD8+ /45RA-/62L- 28.14 133.333 0.00107 32.59 100 0.01939 Table 2. MM n=6-13 NHL n=5-12 Cytokine Baseline cells/mm3 Median % Change from Baseline P Baseline cells/mm3 Median % Change from Baseline P IL-2 98.71 603.509 0.01329 104.5 437.194 0.01761 IL-6 131.84 124.108 0.03426 99.64 21.68 0.2692 GM-CSF 90.24 636.207 0.06608 212.96 144.601 0.16744 IFNg 271.85 404.98 0.0056 554.64 162.451 0.03024 Conclusions: CC-122 significantly increases the proportion of several cytotoxic and helper T cells subsets while decreasing naïve T cells in both DLBCL and MM subjects. CC-122 also significantly activates T cells ex vivo as measured by cytokine production. These results indicate that CC-122 is a potent modulator of T cell numbers and activation and this may serve as rationale for combinations with other immunotherapies. Disclosures Gandhi: Celgene: Employment, Equity Ownership. Off Label Use: CC-122 is a first in class PPM(TM) pleiotropic pathway modifier with multiple biological activities against B lineage cells. Vincent:Pharmamar: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Esai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding. Carpio:Celgene: Research Funding. Stoppa:Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Gharibo:Celgene: Research Funding. Damian:Celgene: Research Funding. Rasco:Celgene: Research Funding; Asana BioSciences, LLC: Research Funding. Ysebaert:Celgene: Research Funding. Cordoba:Celgene: Research Funding. Edenfield:Celgene: Research Funding. Pinto:Celgene Corporation: Honoraria; Takeda: Honoraria, Research Funding; Spectrum: Honoraria. López-Martín:Celgene: Research Funding. Sancho:Celgene: Research Funding. Panizo:Janssen: Speakers Bureau; Takeda: Speakers Bureau; Roche: Speakers Bureau; Celgene: Research Funding. Wei:Celgene: Employment, Equity Ownership. Hagner:Celgene: Employment, Equity Ownership. Waldman:Celgene: Employment, Equity Ownership. Hege:Celgene Corporation: Employment, Equity Ownership. Chopra:Celgene Corporation: Employment, Equity Ownership. Pourdehnad:Celgene: Employment.

A First-in-Human Study of Novel Cereblon Modulator Avadomide (CC-122) in Advanced Malignancies

“…Avadomide also induces apoptosis in multiple myeloma cells and shows antitumor activity in mouse xenograft models of DLBCL and multiple myeloma (6,8,9). In T cells, Aiolos degradation by avadomide leads to derepression of genes, including IL2, resulting in enhanced IL2 production, costimulation of T cells, and IL2-induced T-cell proliferation (1, 5,10). In addition, avadomide has been shown to activate natural killer (NK) cells and exhibits potent antiangiogenic properties, as demonstrated in an ex vivo umbilical artery sprout outgrowth assay (9).…”

“…Current treatment options for patients with advanced solid and hematologic malignancies relapsed or refractory to standard therapies are limited. Avadomide's cell-autonomous effects, immune modulation, and antiangiogenic activity make it a potential therapeutic agent for hematologic and solid tumors (1,2,10,11). Herein, we report results from the first-in-human phase I dose-escalation study of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.…”

Phase I, multicenter, dose‐escalation study of avadomide in adult Japanese patients with advanced malignancies

“…Avadomide also decreased CD19 + B cells and expanded cytotoxic memory T cells in patients with NHL 12,13 . Furthermore, paired biopsies from DLBCL patients showed increased infiltration of T cells and macrophages upon treatment with avadomide 11 . Avadomide has also been shown to activate NK cells that mediate antibody‐dependent, cell‐mediated cytotoxicity 14 .…”

“…In conjunction with antilymphoma activity, avadomide has immunomodulatory effects. Ex vivo studies showed that avadomide significantly activated T cells, as measured by a dramatic increase in IL‐2 secretion upon stimulation 6,11 . Avadomide also decreased CD19 + B cells and expanded cytotoxic memory T cells in patients with NHL 12,13 .…”

“…12,13 Furthermore, paired biopsies from DLBCL patients showed increased infiltration of T cells and macrophages upon treatment with avadomide. 11 Avadomide has also been shown to activate NK cells that mediate antibody-dependent, cell-mediated cytotoxicity. 14 Additionally, avadomide has demonstrated antiangiogenic activity that may make it effective against solid tumors.…”