Abstract
BackgroundNeoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. We hypothesized that neoadjuvant ipilimumab in combination with high dose IFNα2b (HDI) is safe and associated with durable pathologic complete responses (pCR).MethodsPatients with locally/regionally advanced melanoma were randomized to ipilimumab 3 or 10 mg/kg × 4 doses bracketing definitive surgery, then every 12 weeks × 4. HDI was given concurrently. We evaluated the safety and efficacy of the combination with ipilimumab 3 or 10 mg/kg. The impact on T-cell fraction and clonality were investigated in tumor and blood.ResultsThirty patients (age 37–76), 15 each at 3 and 10 mg/kg, 18 male and 12 female were treated. Considering immune related adverse events (irAEs) of interest, more grade 3/4 irAEs were seen with ipilimumab 10 mg/kg versus 3 mg/kg (p = 0.042). Among 28 evaluable patients, 11 relapsed, of whom 5 died. Median follow-up for 17 patients who have not relapsed was 32 months. The radiologic preoperative response rate was 36% (95% CI, 21–54); 4 patients at ipilimumab 3 mg/kg and 6 at 10 mg/kg and 2 (at 10 mg/kg) later relapsed. The pCR was 32% (95% CI, 18–51); 5 patients at ipilimumab 3 mg/kg and 4 at 10 mg/kg and one (at 3 mg/kg) had a late relapse. In patients with pCR, T-cell fraction was significantly higher when measured in primary melanoma tumors (p = 0.033). Higher tumor T-cell clonality in primary tumor and more so following neoadjuvant therapy was significantly associated with improved relapse free survival.ConclusionsNeoadjuvant ipilimumab-HDI was relatively safe and exhibited promising tumor response rates with an associated measurable impact on T-cell fraction and clonality. Most pCRs were durable supporting the value of pCR as a primary endpoint in neoadjuvant immunotherapy trials.Trial registrationClinicalTrials.gov, NCT01608594. Registered 31 May 2012.
Highlights
Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma
In the cytotoxic T-cell compartment, type I IFNs induce antitumor cell-mediated cytotoxicity [21], and promote natural killer (NK) cell-mediated proliferation and cytotoxicity [22]. This Th1 shift in immunity induced by IFNα can be countered by other mechanisms (e.g. CTLA-4) explaining very limited activity observed with IFNα as monotherapy in metastatic melanoma
We previously reported the results of a phase II study of the combination of IFNα-2b and the anti-CTLA4 antibody tremelimumab in patients with advanced inoperable melanoma [23]
Summary
Neoadjuvant immunotherapy utilizing novel combinations has the potential to transform the standard of care for locally/regionally advanced melanoma. The current standard of care consists of aggressive surgical management aimed at rendering the patient disease free surgically, followed by systemic adjuvant therapy [4,5,6,7] For these patients, there continues to be an urgent need to improve the clinical outcome through novel systemic neoadjuvant approaches that may minimize the surgical intervention in an era of unprecedented advances in systemic therapy [8]. Patients with advanced melanoma display strong Th2-type polarization [9, 10] Both CTLA-4 blockade and IFNα can up-regulate the pro-inflammatory cytokine response (Th1 polarization) [11, 12], and are associated with increased T-cell and dendritic cell (DC) tumor infiltration [13,14,15]. Combining IFNα with CTLA-4 blockade may, alter this balance by down-regulating the CTLA4 suppressive regulatory elements
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