Increase in Activated Treg in TIL in Lung Cancer and In Vitro Depletion of Treg by ADCC Using an Antihuman CCR4 mAb (KM2760)

Abstract

The findings suggested the CCR4 on activated/effector Tregs and non-Tregs was functionally involved in the chemokinetic migration and accumulation of those cells to the tumor site. In vitro findings of efficient elimination of Tregs may give the basis for implementation of a clinical trial to investigate Treg depletion by administration of an anti-hCCR4 mAb to solid cancer patients.

Phase Ia Study of FoxP3+ CD4 Treg Depletion by Infusion of a Humanized Anti-CCR4 Antibody, KW-0761, in Cancer Patients

“…CCR4 expression was observed on CD4 T cells, but not on CD8 T cells, NK cells, or B cells. High expression of CCR4 on FoxP3 þ CD4 Tregs was shown previously (8,11). CCR4 expression on Th17 and Th2 was also high, but that on Th1 cells was low.…”

“…The involvement of CCR4 and CCR4-associated chemokines, TARC/CCL17 and MDC/CCL22, for FoxP3 þ Tregs migration has been documented (10). The accumulation of activated/effector Tregs in the tumor site and the production of MDC/CCL22 by intratumor myeloid cells were recently shown in lung cancer (11). FoxP3 þ Tregs inhibit immune responses against tumors and also diminish the immunotherapeutic effects which activate host immune responses.…”

“…Expression of CCR4, NY-ESO-1, and XAGE1 (GAGED2a) was examined by IHC as described previously (11,(19)(20)(21)(22).…”

“…These findings together with recent findings of efficient elimination of FoxP3 þ Tregs by a chimeric anti-human CCR4 mAb (KM2760) suggested its potential use in solid cancer patients (11). To examine selective FoxP3 þ CD4 Tregs depletion in solid cancer patients, we conducted a phase Ia clinical trial of KW-0761 infusion in 10 patients with CCR4-negative lung and esophageal cancers.…”

Low-dose cyclophosphamide depletes circulating naïve and activated regulatory T cells in malignant pleural mesothelioma patients synergistically treated with dendritic cell-based immunotherapy

“…In light of the recent developments in the tumor immunology field, the approved checkpoint inhibitors, against CTLA-4 or PD-(L)1, 15,49,50 or anti-CCR4 antibodies to inhibit aTregs, 51,52 could be interesting methods to reduce the immunosuppressive TME as a synergistic addition to DC-based immunotherapy in mesothelioma, instead of or complementary to surgery and mCTX.…”