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A pilot study of CTLA-4 blockade after cancer vaccine failure in patients with advanced malignancy
Deirdre O'Mahony1, John C Morris, Cate Quinn
1Metabolism Branch, Laboratory of Pathology, Department of Laboratory Medicine, National Eye Institute, Bethesda, MD 20892-1457, USA.
Purpose:
Eleven patients with progressive advanced malignancy after administration of a cancer vaccine received a fully human anti-CTLA-4 monoclonal antibody (ipilimumab). The primary end point was to determine drug toxicity. Tumor response, tumor-specific CD8+ T-cell immune responses, and modulation of CD4+ CD25+ FoxP3+ regulatory T-cell (Treg) numbers were secondary end points.
Experimental Design:
Three patients with colon cancer, four with non-Hodgkin's lymphoma, and four with prostate cancer were treated. The first dose was given at 3 mg/kg and subsequent doses were administered monthly at 1.5 mg/kg for a total of four cycles.
Results:
Tumor regression was observed in two patients with lymphoma; one of which obtained a partial response of 14-month duration. Ipilimumab was well tolerated with predominantly grade 1/2 toxicities. One drug-related grade 3 toxicity was observed. One patient died within 30 days of treatment due to progressive colon cancer. No increase in vaccine-specific T-cell responses was observed after therapy. Tregs as detected by expression of CD4+CD25+CD62L+ declined at early time points but rebounded to levels at or above baseline values at the time of the next infusion.
Conclusions:
Ipilimumab treatment depressed Treg numbers at early time points in the treatment cycle but was not accompanied by an increase in vaccine-specific CD8+ T-cell responses in these patients previously treated with a variety of investigational anticancer vaccines. A partial response was observed in one patient with follicular lymphoma. A phase I/II trial evaluating ipilimumab in patients with follicular lymphoma is currently ongoing.
Insights
Ipilimumab (anti-CTLA-4 antibody) showed manageable toxicity in advanced cancer patients previously treated with vaccines. While it transiently reduced regulatory T-cells, it did not boost vaccine-specific T-cell responses, though one lymphoma patient had a partial response.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Cancer vaccines are investigated for advanced malignancies.
- Immune checkpoint inhibitors, like ipilimumab (anti-CTLA-4), modulate T-cell responses.
- Regulatory T-cells (Tregs) can suppress anti-tumor immunity.
Purpose of the Study:
- To assess the toxicity of ipilimumab in patients with advanced cancer post-vaccine therapy.
- To evaluate tumor response and immune modulation, including CD8+ T-cells and Tregs, as secondary endpoints.
Main Methods:
- Eleven patients with advanced cancers (colon, lymphoma, prostate) received ipilimumab.
- Treatment involved an initial dose of 3 mg/kg followed by monthly 1.5 mg/kg doses for four cycles.
- Tumor response, CD8+ T-cell and Treg (CD4+CD25+FoxP3+) dynamics were monitored.
Main Results:
- Ipilimumab was generally well-tolerated with mostly grade 1/2 toxicities; one grade 3 event occurred.
- Tumor regression was seen in two lymphoma patients, one with a 14-month partial response.
- No increase in vaccine-specific CD8+ T-cell responses was observed; Tregs transiently decreased then rebounded.
Conclusions:
- Ipilimumab treatment in vaccine-experienced patients reduced Tregs early in cycles but did not enhance vaccine-specific CD8+ T-cell immunity.
- A partial response was noted in one follicular lymphoma patient.
- A Phase I/II trial of ipilimumab for follicular lymphoma is ongoing.
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