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Overcoming the ‘don’t eat me signal’ in patients with refractory lymphoma

A combination of rituximab with the first in class anti-CD47 agent Hu5F9-G4 induces durable responses in both heavily pre-treated patients with diffuse large B-cell lymphoma or indolent lymphoma. This is demonstrated by results of a phase I/II study. CD47 is a cell surface glycoprotein that is exploited by cancer cells to evade immunological eradication. By blocking CD47, the ‘don’t eat me signal’ on cancer cells is removed allowing their phagocytosis by the immune system.


Over the last decades very effective chemotherapy schemes have been developed for patients with non-hodgkin's lymphoma. In aggressive lymphomas, such as diffuse large B-cell lymphoma (DLBCL), first-line chemotherapy cures half of the patients, while in indolent lymphomas (such as follicular lymphoma; FL) frontline chemotherapy induces a remission in the majority of patients. For patients who do not respond to chemotherapy (refractory), or who relapse after a certain amount of time the situation looks much grimmer. As such, there is a need for new therapeutic strategies that are able to overcome this treatment resistance. Hu5F9-G4 is a first-in-class IgG4 antibody targeting CD47, a macrophage immune checkpoint with a central role in immunological self-recognition that sends a ‘don’t eat me’ signal to immune cells. Many solid and haematological cancers exploit this immune checkpoint and express CD47 on their cell surface to avoid immunological eradication. Moreover, a high expression of CD47 was found to be associated with a worse prognosis in patients with B-cell non-hodgkin lymphoma. Pre-clinically, Hu5F9-G4 was found to synergise with rituximab in eliminating lymphoma cells by enhancing antibody-dependent cellular phagocytosis. Hu5F9-G4 plus rituximab also demonstrated encouraging safety and efficacy in a phase Ib dose escalation study in patients with relapsed/refractory (r/r) DLBCL and rituximab-refractory FL. During EHA 2019, extended follow up data of this phase 1b cohort were presented in addition to and preliminary results of the phase II part of this study

Study design and results

The study enrolled DLBCL patients who were primary refractory or relapsed/refractory to at least 2 prior therapies and who were ineligible for CAR-T therapy in addition to indolent lymphoma (FL and marginal zone lymphoma; MZL) patients who also had to be relapsed/refractory to at least 2 prior therapies. Based on a potential dose-response seen in the phase 1b trial, Hu5F9-G4 doses of 30 and 45 mg/kg were tested with rituximab.

A total of 115 patients (70 DLBCL, 41 FL, 4 MZL) have been treated across the phase Ib and II studies. The median age of the patients in the trial was 66 years and patients received a median of 3 prior therapies (ranging from 1-10). Overall, 85% of enrolled patients were rituximab-refractory and 72% were refractory to their last line of therapy. Overall, the Hu5F9-G4 + rituximab combination was well tolerated at Hu5F9-G4 doses of up to 45 mg/kg (maximum tolerated dose not reached). No significant dose-dependent toxicities were observed. Treatment-related adverse events (AEs) occurring in >10% of patients included infusion reactions (38%), headache (34%), chills (30%), fatigue (30%), anaemia (27%), nausea (24%), pyrexia (23%) vomiting (13%) and back pain (11%). Interestingly, the majority of these AEs were grade 1 and 2 in severity. The only grade 3/4 AE observed in more than 7% of patients was anaemia (15%), but this was an expected transient first-dose effect. Treatment discontinuation due to drug-related AEs occurred in only 8/115 (7%) patients.

Of the 115 patients enrolled in the study, 97 were evaluable for efficacy. Among these 97 patients, an objective response rate (ORR) of 45% was reported with a CR in 19%. Not surprisingly, the response rates were higher among the indolent lymphoma patients (FL N=35, MZL N=3) where an ORR and CR rate was reported of 61% and 24%, respectively. Among DLBCL patients (N=59), the ORR was 36% including a CR in 15% of patients. The median time to response for responding patients was rapid at 1.8 months. At a median follow-up of up to 13 (DLBCL) and 21 months (FL) for patients treated with 10-30 mg/kg (N=22) of Hu5F9-G4 in the phase 1b cohort, the median duration of response had not been reached (duration of response in DLBCL patients ranged from 3.6 to more than 23.8 months and from 6.2 to more than 27.6 months in FL patients). Interestingly, several sustained complete responses (CR) of more than 20 months were observed


The presented results convincingly demonstrate the safety and efficacy of the Hu5F9-G4 + rituximab combination in both heavily pre-treated DLBCL and indolent lymphoma patients. Further enrolment in the phase II part of this trial is ongoing. As such, this approach represents a promising new immune checkpoint inhibition strategy. It is to be expected that the potential of CD47 targeting will also be explored on other tumour types.


Advani R, Bartlett N, Smith S, et al. The first-in-class anti-CD47 antibody HU5F9-G4 with rituximab induces durable responses in relapsed/refractory DLBCL and indolent lymphoma: interim phase 1B/2 results. Presented at EHA 2019; abstract S867.

Speaker Mark Roschewski


Mark Roschewski, MD, Center for Cancer Research, National Cancer Institute, Bethesda, USA


See: Keyslides


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