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. 2023 May 15;29(10):1869-1878.
doi: 10.1158/1078-0432.CCR-22-2955.

Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma

Julio C Chavez  1 , Francine M Foss  2 , Basem M William  3 , Jonathan E Brammer  3 , Sonali M Smith  4 , Anca Prica  5 , Jasmine M Zain  6 , Joseph M Tuscano  7 , Harsh Shah  8 , Neha Mehta-Shah  9 , Praveen Ramakrishnan Geethakumari  10 , Ben X Wang  11 , Stephanie Zantinge  5 , Lisa Wang  12 , Ling Zhang  13 , Anmarie Boutrin  14 , Weiguang Zhao  14 , Lily Cheng  15 , Nathan Standifer  16 , Lisa Hewitt  17 , Enowmpey Enowtambong  17 , Weiping Shao  17 , Shringi Sharma  18 , Gianluca Carlesso  19 , Jeffrey A Moscow  20 , Lillian L Siu  5   11
Affiliations

Targeting the Inducible T-cell Costimulator (ICOS) in Patients with Relapsed/Refractory T-follicular Helper Phenotype Peripheral T-cell and Angioimmunoblastic T-cell Lymphoma

Julio C Chavez et al. Clin Cancer Res. .

Abstract

Purpose: Proliferation of T-follicular helper (TFH) CD4+ T cells is a postulated pathogenic mechanism for T-cell non-Hodgkin lymphomas (T-NHL). The inducible T-cell costimulator (ICOS) is highly expressed by TFH, representing a potential target. MEDI-570 is a monoclonal antibody against ICOS, which eliminates ICOS+ cells in preclinical models.

Patients and methods: We report the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of MEDI-570 in T-NHL. NCI-9930 is a phase I, first-in-human study of MEDI-570 in relapsed/refractory malignant T-NHL known to express ICOS. MEDI-570 was administered intravenously every 3 weeks for up to 12 cycles. Primary endpoints were safety, dose-limiting toxicities (DLT), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included efficacy parameters and various correlative studies. This study is supported by the National Cancer Institute (NCT02520791).

Results: Twenty-three patients were enrolled and received MEDI-570 at five dose levels (0.01-3 mg/kg). Sixteen (70%) had angioimmunoblastic T-cell lymphoma (AITL); median age was 67 years (29-86) and the median prior lines of therapies was 3 (1-16). Most common grade 3 or 4 adverse events were decreased CD4+ T cells (57%), lymphopenia (22%), anemia (13%), and infusion-related reactions (9%). No DLTs were observed. The RP2D was determined at 3 mg/kg. Analysis of T-cell subsets showed reductions in CD4+ICOS+ T cells reflecting its effects on TFH cells. The response rate in AITL was 44%.

Conclusions: MEDI-570 was well tolerated and showed promising clinical activity in refractory AITL. MEDI-570 resulted in sustained reduction of ICOS+ T lymphocytes.

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Figures

Figure 1.
Figure 1.. A) Waterfall plot by dose level. B) waterfall plot by histology. C) spider plot by dose level. D) spider plot by histology
Figure 1.
Figure 1.. A) Waterfall plot by dose level. B) waterfall plot by histology. C) spider plot by dose level. D) spider plot by histology
Figure 1.
Figure 1.. A) Waterfall plot by dose level. B) waterfall plot by histology. C) spider plot by dose level. D) spider plot by histology
Figure 1.
Figure 1.. A) Waterfall plot by dose level. B) waterfall plot by histology. C) spider plot by dose level. D) spider plot by histology
Figure 2.
Figure 2.. Serum concentration (Mean±SD) versus time profile for MEDI-570 following IV administration of MEDI-570 monotherapy
Figure 3.
Figure 3.. MEDI-570 induces reductions in CD3+CD4+ T cells and subsets that are associated with dose level.
Baseline-normalized, absolute counts (ABS) of circulating CD3+CD4+ T cell populations were plotted on study days 1, 7, 14 and 21 from patients enrolled in each dose group as indicated. A) CD3+CD4+CD278+ T cells B) Total CD3+CD4+ T helper cells C) CD3+CD4+CD45RA− memory T cells and D) CD3+CD4+CD45RA-CD183-CD185+ T follicular helper T cells.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
Figure 4.
Figure 4.. Flow cytometry analysis of the peripheral immune composition in AITL, CTCL and PTCL patients.
A) Comparison of peripheral CD3+, CD3+CD4+ and CD3+CD8+ T cells from all patients at screening (S), cycle 1 week 1 (C1W1), cycle 1 week 3 (C1W3) and cycle 2 week 1 (C2W1). p values are indicated (paired t test). B) Panel 1 and C) panel 2 data from all patients and time points were pooled, and computational clustering using all markers was performed using Rphenograph and visualized using UMAP. For each panel, UMAPs were generated to compare the baseline (S or C1W1) immune profiles of patients by D-E) diagnosis and F-G) best response.
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