Page 1551 - Hematology_ Basic Principles and Practice ( PDFDrive )

1378 Part VII Hematologic Malignancies

NCT02314247). Direct targeting of surface receptors of the neoplas- KIR3DL2 acts as an inhibitory coreceptor by its ability to down-
tic cells with monoclonal antibodies continues to represent a common modulate CD3-dependent early signaling events and may be respon-
investigative approach, with a number of new molecules described sible for maintaining a high circulating malignant cell burden by
later. preventing activation-induced cell death.
In support of the clinical investigation of the humanized anti-
KIR3DL2 antibody, IPH4102, as a treatment for SS and tMF,
Anti-CCR4 Monoclonal Antibody Marie-Cardine et al demonstrated a correlation between KIR3DL2
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expression and TCR-Vβ clonality on circulating CD4 T cells from
As already discussed, KW-0761 (mogamulizumab) is a humanized 32 SS patients (Spearman r = 0.6609, p < .0001). Among blood
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defucosylated anti-CCR4 monoclonal antibody that has been samples from 35 healthy volunteers, CD4 KIR3DL2 T cells com-
approved in Japan for the treatment of ATL. CCR4, often expressed prised 1.4%. Among six SS patient samples, costaining with IPH4102
by CTCL cells, contributes to the skin-homing ability of the CTLC bound to R-Phycoerythrin and anti-TCR-VB antibody showed
cells. Defucosylation of the Fc region of the agent allows for a greater consistent and homogeneous staining of the Sézary cells. A small
binding affinity to the Fcγ receptor of effector cells, resulting in population of TCR-negative cells stained positive for IPH4102,
antibody-dependent cell-mediated cytotoxicity (ADCC). Among 21 reflecting the normal NK cell population. ADCC and antibody-
MF and 17 SS patients in a phase I/II multicenter study, KW-0761 dependent PMN-mediated cytotoxicity, using allogeneic NK cells,
0.1 mg/kg, 0.3 mg/kg or 1 mg/kg administered weekly resulted in were demonstrated using an SS cell line treated with IPH4102.
an overall RR of 37% in the total intention-to-treat population. Complement-dependent cytotoxicity, however, was not observed. In
Interestingly, when measured by immunohistochemistry on skin vivo antitumor efficacy was demonstrated in patient-derived xeno-
biopsy samples and flow cytometric analysis of peripheral blood, graft murine models with solid and disseminated disease, with tumor
CCR4 expression did not correlate with response to therapy. Ishii reduction and improvement in survival demonstrated. Furthermore,
et al observed that the degree of KW-0761-mediated ADCC against IPH4102 showed in vitro ADCC among patient samples when using
ATL cells was determined primarily by the number of effector NK autologous NK cells. Lastly, despite that NK cells express KIR3DL2,
cells present rather than by the amount of CCR4 present on the ATL the NK cells were spared from the cytotoxic effects of IPH4102 in
surface. These observations may support the study of NK cell quan- this study, whereas alemtuzumab led to the elimination of NK cells.
tification as a biomarker of efficacy of KW-0761 and may support Altogether, this series of experiments demonstrate that Sézary cells
the study of the combination of KW-0761 with an NK cell-enhancing are sensitive to ADCC mediated by IPH4102 through KIR3DL2
immunomodulatory drug such as lenalidomide. KW-0761 was also targeting at their surface; circulating NK cells of SS patients are
evaluated in a multicenter phase II study of 37 relapsed PTCL or functional and able to mediate potent IPH4102-directed ADCC; and
CTCL (n = 8) patients who received the drug weekly at 1.0 mg/kg IPH4102 antitumor activity is selectively targeted against KIR3DL2-
for 8 weeks. Overall, there was a 35% RR and a median PFS of 3 expressing tumor cells and spares NK effectors. IPH4102 has received
months, and among the eight CTCL patients, three had a PR, four orphan drug designation by the European Commission for the treat-
had stable disease (SD), and one progressed. AEs consisted of ment of CTCL, and a phase I trial is expected to start in the near
cytopenias, pyrexia, and skin disorders. A phase III multicenter trial future.
is currently enrolling relapsed/refractory CTCL patients for ran-
domization to KW-0761 or vorinostat (ClinicalTrials.gov identifier:
NCT01728805). Anti-PD-1/PD-L1 Therapy

Given the established role of multiple forms of immunotherapy, such
Anti-CD3ε Immunotoxin as IFN, extracorporeal photophoresis, and aSCT, in the treatment of
CTCL, and the mounting supportive preclinical data, the investiga-
Resimmune (A-dmDT390-bisFv[UCHT1]) is a recombinant anti- tion of the use of anti–PD-1/PDL1 therapy for CTCL is warranted.
CD3ε immunotoxin that is composed of the catalytic and transloca- Conceptually, checkpoint blockade therapy differs from more tradi-
tion domains of diphtheria toxin fused to two antihuman CD3ε Fv tional forms of immunotherapy, such as IFN-α and high-dose IL-2,
fragments. In a phase I study the agent was administered to 25 CTCL by blocking the inhibitory controls (i.e., PD-1) of T cells rather than
patients, most of whom had been previously treated, at doses ranging inducing brief periods of immunostimulation. This approach may
from 2.5 to 11.25 µg/kg intravenously twice daily for 4 consecutive overcome immunosuppression and thereby lead to more durable
days. Nine patients (36%) experienced a response, four of which were control of disease and improved survival. High expression of PD-1
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complete (16%). The durations of the CRs were 72+, 72+, 60+, and has been noted among CD4 T cells from SS patients, compared with
38+ months. Some patients in this study slowly converted from PR the cells of early-stage MF patients and healthy donors in multiple
to CR even after receiving treatment. Patients with a lower tumor studies. In vitro antibody blockade of PD-1 and PD-L1 from periph-
burden were more likely to respond. AEs were mild to moderate and eral blood mononuclear cells of CTCL patients resulted in increased
included fevers, chills, hypotension, hypoalbuminemia, edema, production of IFN-γ, a cytokine associated with Th1 antitumor
hypophosphatemia, viral reactivation, and transaminitis. The phase immunity. The cytolytic activity of PD-L1–specific T cells against
II portion of this study is actively enrolling patients. PD-L1–positive human CTCL cells and the lack of activity against
PD-L1–negative human CTCL cells have also been demonstrated,
but the use of PD-L1 as a predictive biomarker of response has not
Anti-KIR3DL2 Therapy been validated. In immunophenotyping studies of freshly isolated
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malignant CD4 T cells and tumor-infiltrating CD8 T cells from
As already mentioned, KIR3DL2 (CD158k) represents a unique cell CTCL patients, both cell lines displayed enhanced expression of
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surface target among the malignant CD4 T cells from SS patients PD-1 and other immune checkpoint proteins, consistent with
and tMF patients. KIR3DL2, which belongs to the inhibitory KIR immune exhaustion and suggestive that checkpoint blockade therapy
family and is normally detectable on a minor subset of NK cells and may be beneficial in these patients. Recently presented data regarding
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on a rare subset of CD3 CD8 circulating T cells, has ligand specific- the relationship between the mutational burden of some malignancies
ity for HLA-A3 and HLA-A11 through a peptide-specific interaction and response to anti–PD-1 antibody therapy support the investiga-
and for HLA-B27 homodimer through peptide-independent recog- tion of mutational burden, directly assessed by sequencing or indi-
nition. CpG oligodeoxynucleotides have been shown to act as a rectly assessed by mismatch repair status, as a predictive marker to
ligand to KIR3DL2 on NK cells as well as on Sézary cells, resulting anti–PD-1/PD-L1 therapy in CTCL. In a phase I study of anti–PD-1
in downmodulation of KIR3DL2 from the cell surface and induction antibody nivolumab to treat hematologic malignancies, PRs were
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of cytokine release. Among malignant CD4 cells of SS and tMF, observed in two of 13 MF patients, while some others experienced