Phase I(b) study evaluating the safety and efficacy of intratumoral agonistic anti-CD40 (selicrelumab) in combination with anti-PD-L1 (atezolizumab) in patients with refractory or relapsed B-cell lymphoma (ITSELF trial)

Background

The efficacy of immune checkpoint blockade therapy requires pre-existing antitumor immunity. Defective antigen presentation during the priming phase can reduce the generation of tumor-specific T cells, which are necessary during the effector phase and subsequent tumor elimination. We propose an in situ immunization strategy to enhance direct tumor antigen presentation by the lymphoma B cells via cluster of differentiation (CD)40 stimulation in order to sensitize B-cell lymphoma to programmed cell death protein 1/programmed death-ligand 1 (PD-L1) blockade therapy.

Materials and methods

ITSELF is a multicenter, open-label, dose-escalation phase Ib trial of intratumoral selicrelumab, an agonistic anti-CD40 monoclonal antibody, every 3 weeks for three cycles in combination with intravenous atezolizumab, an antagonistic anti-PD-L1 monoclonal antibody, at 1200 mg every 3 weeks for three cycles followed by intravenous atezolizumab monotherapy for a total of 12 months in patients with relapsed/refractory B-cell lymphoma.

Results

Two patients with follicular lymphoma and two patients with diffuse large B-cell lymphoma were enrolled at the first dose level of 1 mg intratumoral selicrelumab. Those four patients received the three cycles of intratumoral selicrelumab in combination with intravenous atezolizumab. Patients did not develop severe adverse events related to the drugs or the intratumoral procedures. No or low-grade adverse events were reported and related to atezolizumab or to the combination therapy. All patients discontinued the treatment because of disease progression according to Lugano 2014 criteria on their first positron emission tomography scan disease evaluation at the end of cycle 3 (week 9). The trial was stopped prematurely because of issues with selicrelumab drug supply.

Conclusion

The combination of 1 mg of intratumoral selicrelumab and 1200 mg of intravenous atezolizumab was safe for patients with relapsed/refractory B-cell lymphoma and led to some tumor stabilization or regression, although it did not result in objective tumor response.