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Unmasking the immune recognition of prostate cancer with CTLA4 blockade.

ABSTRACT: Although cancer cells can be immunogenic, tumour progression is associated with the evasion of immunosurveillance, the promotion of tumour tolerance and even the production of pro-tumorigenic factors by immune cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) represents a crucial immune checkpoint, the blockade of which can potentiate anti-tumour immunity. CTLA4-blocking antibodies are now an established therapeutic approach for malignant melanoma, and clinical trials with CTLA4-specific antibodies in prostate cancer have also shown clinical activity. This treatment may provide insights into the targets that the immune system recognizes to drive tumour regression, and could potentially improve both outcome and toxicity for patients with prostate cancer.

SUBMITTER: Kwek SS

PROVIDER: S-EPMC3433280 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature

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Unmasking the immune recognition of prostate cancer with CTLA4 blockade.

Kwek Serena S SS Cha Edward E Fong Lawrence L

Nature reviews. Cancer 20120301 4

Although cancer cells can be immunogenic, tumour progression is associated with the evasion of immunosurveillance, the promotion of tumour tolerance and even the production of pro-tumorigenic factors by immune cells. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) represents a crucial immune checkpoint, the blockade of which can potentiate anti-tumour immunity. CTLA4-blocking antibodies are now an established therapeutic approach for malignant melanoma, and clinical trials with CTLA4-specifi ...[more]

PMID: 22378189

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Project description:BackgroundWe previously reported early on-treatment significant modulation in circulating regulatory T cell (Treg), myeloid derived suppressor cells (MDSC) and antigen-specific type I CD4+ and CD8+ T cells that correlated with clinical outcome in regionally advanced melanoma patients treated with neoadjuvant ipilimumab. Here, we investigated the long term immunologic impact of CTLA4 blockade.MethodsPatients were treated with ipilimumab given at 10 mg/kg IV every 3 weeks for 2 doses bracketing surgery. Blood specimens were collected at baseline and during treatment for up to 9 months. We tested immune responses at 3, 6, and 9 months utilizing multicolor flow cytometry. We compared frequencies of circulating Treg and MDSC on-study to baseline levels, as well as frequencies of CD4+ and CD8+ T cells specific to shared tumor-associated antigens (Gp-100, MART-1, NY-ESO-1).ResultsLevels of Treg significantly increased when measured at 6 weeks following ipilimumab but returned to baseline by 3 months, with no significant difference in Treg levels between relapsed and relapse-free groups at 3, 6 or 9 months. However, lower baseline levels of circulating Treg (CD4+CD25hi+CD39+) were significantly associated with better relapse free survival (RFS) (p = 0.04). Levels of circulating monocytic HLA-DR+/loCD14+ MDSC were lower at baseline in the relapse-free group and further decreased at 6 weeks, though the differences did not reach statistical significance including measurements at 3, 6 or 9 months. We detected evidence of type I (interferon-γ producing), activated (CD69+) CD4+ and CD8+ antigen-specific T cell immunity against cancer-testis (NY-ESO-1) as well as melanocytic lineage (MART-1, gp100) antigens in the absence of therapeutic vaccination. These responses were significantly boosted at 6 weeks and persisted at 3, 6 and 9 months following the initiation of ipilimumab.ConclusionsLower Treg levels at baseline are significantly associated with RFS and increased Treg frequency after CTLA4 blockade was only transient. Lower MDSC was also associated with RFS and MDSC levels were further decreased after ipilimumab. Tumor specific effector immune responses are boosted with CTLA4 blockade and tend to be durable. Trial registration ClinicalTrials.gov Identifier: NCT00972933.

Project description:PurposeTranslational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI).Patients and methodsClinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS).ResultsOf 52 patients with CDK12-mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-näıve versus chemotherapypretreated patients (median PFS: not reached v 2.1 months, P = .004).ConclusionCDK12 mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti-programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.

Dataset Information

Unmasking the immune recognition of prostate cancer with CTLA4 blockade.

Publications

Unmasking the immune recognition of prostate cancer with CTLA4 blockade.

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