Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Abstract

We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

In-situ vaccination using focused ultrasound heating and anti-CD-40 agonistic antibody enhances T-cell mediated local and abscopal effects in murine melanoma

“…Similarly, another study showed that anti-CD40 antibody and 5 Gy total body irradiation (TBI) increased Tcell-mediated survival by 100 days in murine B-cell lymphoma [23]. Additionally, a recent phase 1 clinical trials with anti-CD-40 and anti-CTLA-4 therapy in malignant melanoma caused the activation of cytotoxic immune cells and achieved an objective response rate of 27.3% [18]. These promising findings highlight the important role of anti-CD40 in augmenting therapeutic outcomes in the combinatorial regimen, and a need to conduct additional studies in various tumor types with FUS.…”

“…Some studies have also shown that the systemic administration of CD-40 agonists lowers the intratumoral PD-1 expression in T-cells, and aid the phenotypic conversion of macrophages from M2 to M1 [15][16][17]. Currently, several clinical trials are investigating the role of anti-CD40 in various tumor types (NCT02376699, NCT03389802, NCT03123783, NCT03597282 NCT03165994, NCT02706353) [18,19]. FUS-induced local heating and associated stress can modify the tumor cells and microenvironment, causing antigen release, expression of heat-shock proteins, upregulation of pro-phagocytic signals such as calreticulin (CRT), and overall stimulate tumor immunity.…”

The role and therapeutic implications of T cells in cancer of the lung

“…A phase-I clinical trial combining aCD40 (CP-870,893) + aCTLA-4 (tremelimumab) observed 27.3% of metastatic melanoma patients (n = 24) to achieve an objective response, with two complete responses observed. 48 Unfortunately, trials investigating aCD40 therapy in NSCLC are currently limited; however, clinical trials are ongoing for dual aCD40 (APX005M) + nivolumab in advanced NSCLC (NCT03123783).…”

Insights Into Lung Cancer Immune-Based Biology, Prevention, and Treatment

“…Nivolumab along with ipilimumab concurrent therapy for late stage melanoma patients achieved clinical success, including improved objective response rate, progression free survival, a stable improvement in survival benefit, and reduced toxicity in comparison to patients receiving nivolumab alone (134,142,(149)(150)(151). Improved response to dual ICB seemed to override the need for abundant PD-L1 expression observed in monotherapy, whilst high TMB and improved response correlated wellacross the dual ICB group (134).…”