Development of a PD-1-abrogating IgG4 monoclonal antibody: nivolumab

Transgenic mice expressing human immunoglobulin loci were injected with PD-1-expressing cells and fully human anti-PD-1 antibodies were produced.25 Binding of each antibody with PD-1 and lack of binding with other immune checkpoint inhibitor was checked. A monoclonal anti-PD-1 antibody was chosen for its high affinity for PD-1. This fully human IgG4 anti-PD-1 antibody was changed into an IgG4 antibody with a hinge mutation (S228P) to reduce binding to Fc receptors (nivolumab).

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Nivolumab activates human melanoma antigen-specific cytotoxic T-lymphocytes

Wong et al added the nivolumab into the culture medium and examined the number of cytotoxic T-lymphocytes against human melanoma associated antigens, melanoma antigen recognized by T-cells (MART)-1, and glycoprotein 100 (gp100).6,25–27 They found that administration of nivolumab resulted in the increase in the number of MART-1- or gp100-responsive cytotoxic T-lymphocytes. Cytokine production by T-lymphocytes was also increased by the addition of nivolumab.

Initial studies on nivolumab for malignant tumors

Brahmer et al studied the effect of nivolumab for 39 patients with malignant tumors including colorectal cancer (CRC), advanced metastatic melanoma, prostate cancer, non-small-cell lung cancer, and renal cell carcinoma.28 Nivolumab was well tolerable and the serum half-life of nivolumab was found to be 12–20 days.

One patient with CRC showed durable complete response, and one patient with malignant melanoma and another patient with renal cell carcinoma showed partial responses.

Based upon the Phase I study on effects, safety, and tolerability of nivolumab against malignant tumors described above, Topalian et al studied the effects of nivolumab for 296 patients with malignant tumors.29

In total, 41% of the patients showed treatment-related adverse events: nine patients with pneumonitis, four patients with allergic rhinitis, 33 patients with diarrhea, 36 patients with rash, 28 patients with pruritus, eleven patients with increased alanine aminotransferase, nine patients with increased thyroid-stimulating hormone, eight patients with aspartate aminotransferase, seven patients with hypothyroidism, three patients with hyperthyroidism, and nine cases with infusion-related reaction or hypersensitivity.

Objective responses (complete response or partial response) were observed in 26 of 94 patients (29%, 19%, 30%, 41%, and 20% at a dose of 0.1 mg/kg, 0.3 mg/kg, 1.0 mg/kg, 3.0 mg/kg, and 10.0 mg/kg, respectively). Progression-free survival rate at 24 weeks was 41% for malignant melanoma patients.

The median PD-1 receptor occupancy rate in peripheral blood mononuclear cells by nivolumab after one cycle of nivolumab treatment was 64%–70% for malignant melanoma patients.

Immunohistochemical study revealed that 25 of the 42 examined malignant tumor specimens were positive for PD-L1 expression. Of these 25 patients, nine (36%) had an objective response, whereas there was no objective response among the 17 patients with PD-L1-negative tumors, indicating that nivolumab is more likely to be effective for PD-L1-positive tumors than for PD-L1-negative tumors.

Several things have been kept in mind when interpreting these data. First, the expression of PD-L1 can be increased by phosphoinositide-3 kinase and other pathways irrelevant of T-cell infiltration or antitumor immune response. In this case, PD-L1-positive tumors will not be necessarily anti-PD1 therapy.

Second, some patients without PD-L1 expression have been shown to respond to anti-PD1 therapy in other reports. There are several possible explanations for this phenomenon. First, there is a heterogeneity of the tumor in the expression level of PD-L1 and tumor biopsies are not representative of the whole tumor. Secondly, the expression of PD-L1 is dynamic and inducible by some cytokines like IFN-γ secreted by immune cells. Therefore, reactivation of CD8+ T-cells in the tumor will induce higher expression of PD-L1 compared to the baseline expression of PD-L1, when tumor biopsies are performed. Thirdly, due to the technical limitation of immunohistochemical PD-L1 detection system, some weakly PD-L1-expressing tumors can be classified into PD-L1-negative tumors.

Combination therapy with nivolumab and ipilimumab for melanoma

Ipilimumab is a fully human IgG1 monoclonal antibody against another immune checkpoint inhibitor, CTLA4. Administration of ipilimumab for advanced melanoma improved overall survival.30,31 Wolchok et al conducted a Phase I trial of nivolumab combined with ipilimumab for advanced melanoma.32

In total, 86 patients were enrolled in the study. Fifty-three patients received nivolumab and ipilimumab every 3 weeks for 12 weeks and nivolumab alone (concurrent regimen). Thirty-three patients pretreated with ipilimumab received nivolumab every 2 weeks (sequenced regimen).

Among the concurrent regimen group, 21 (40%) out of 53 patients showed objective responses. Among the sequenced regimen group, six (20%) out of 30 patients showed objective responses.

Based upon the above-mentioned result of the Phase I study of combination therapy of nivolumab and ipilimumab, Postow et al performed a double-blind study and concluded that combination therapy with nivolumab and ipilimumab is statistically significantly more effective than an ipilimumab monotherapy.33