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denotes that this is a ticketed session.Program: Oral and Poster Abstracts
Session: 623. Lymphoma: Chemotherapy, excluding Pre-Clinical Models: Poster II
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 .
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