Expanded phase I combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHPRC)

Gerritsen, W.R.; Eertwegh, Alfons J. van den; Gruijl, Tanja D. de; Berg, H. Pieter van den; Scheper, R.J.; Sacks, N.; Lowy, Israel; Stankevich, Elizabeth; Hege, K.

doi:10.1200/jco.2008.26.15_suppl.5146

Cited by 37 publications

(19 citation statements)

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“…In these studies, allogeneic cancer cells transfected with GM-CSF (GVAX) have been evaluated in patients with metastatic pancreatic cancer and hormone-refractory prostate cancer in combination with ipilimumab [93]. In a prostate cancer trial, combination therapy resulted in 4 out of 16 patients achieving evidence of clinical benefit, as measured by PSA response or stabilization [94]. In the pancreatic cancer study, patients who received GVAX with ipilimumab demonstrated evidence of clinical benefit, three out of 15 patients having prolonged disease stabilization, and 7 out of 15 patients experiencing tumor marker declines [93].…”

Section: Combining With Cancer Vaccine Therapymentioning

confidence: 99%

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

2016

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The emergence of immune ‘checkpoint inhibitors’ such as cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed death receptor 1 (PD-1) has revolutionized treatment of solid tumors including melanoma, lung cancer, among many others. The goal of checkpoint inhibitor combination therapy is to improve clinical response and minimize toxicities. Rational design of checkpoint combinations considers immune-mediated mechanisms of antitumor activity: immunogenic cell death, antigen release and presentation, activation of T-cell responses, lymphocytic infiltration into tumors and depletion of immunosuppression. Potential synergistic combinations include checkpoint blockade with conventional (radiation, chemotherapy and targeted therapies) and newer immunotherapies (cancer vaccines, oncolytic viruses, among others). Reliable biomarkers are necessary to define patients who will achieve best clinical benefit with minimal toxicity in combination therapy.

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Section: Combining With Cancer Vaccine Therapymentioning

confidence: 99%

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

2016

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“…Ipilimumab, nivolumab, and pembrolizumab are immune checkpoint therapies that induce durable antitumor responses and improve survival in melanoma (1)(2)(3)(4), nonsmall cell lung cancer (NSLC) (5,6), and renal cell carcinoma (RCC) (7). Clinical trials with ipilimumab in men with castration-resistant prostate cancer (CRPC) have reported limited efficacy to date (1,2,(8)(9)(10)(11)(12). We hypothesized that adding ipilimumab shortly after the start of androgen deprivation therapy (ADT) in men with metastatic prostate cancer, before the disease becomes castration resistant, would enhance the efficacy of the treatment.…”

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confidence: 99%

Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities

Subudhi

Aparicio

Gao

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

199

117

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Immune checkpoint therapies, such as ipilimumab, induce dramatic antitumor responses in a subset of patients with advanced malignancies, but they may also induce inflammatory responses and toxicities termed immune-related adverse events (irAEs). These irAEs are often low grade and manageable, but severe irAEs may lead to prolonged hospitalizations or fatalities. Early intervention is necessary to minimize morbidities that occur with severe irAEs. However, correlative biomarkers are currently lacking. In a phase II clinical trial that treated 27 patients with metastatic prostate cancer, we aimed to test the safety and efficacy of androgen deprivation therapy plus ipilimumab. In this study, we observed grade 3 toxicities in >40% of treated patients, which led to early closure of the study. Because ipilimumab enhances T-cell responses, we hypothesized that increased clonal T-cell responses in the systemic circulation may contribute to irAEs. Sequencing of the T-cell receptor β-chains in purified T cells revealed clonal expansion of CD8 T cells, which occurred in blood samples collected before the onset of grade 2–3 irAEs. These initial results suggested that expansion of ≥55 CD8 T-cell clones preceded the development of severe irAEs. We further evaluated available blood samples from a second trial and determined that patients who experienced grade 2–3 irAEs also had expansion of ≥55 CD8 T-cell clones in blood samples collected before the onset of irAEs. We propose that CD8 T-cell clonal expansion may be a correlative biomarker to enable close monitoring and early intervention for patients receiving ipilimumab.

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“…120 In a separate phase I study, the combination of ipilimumab and vaccination with GVAX was studied in patients (n=12 in phase I; expansion cohort, n=16) with chemotherapy-naive metastatic hormoneresistant prostate cancer and immunotherapy-naive metastatic hormone-resistant prostate cancer. 123 A PSA decline of >50% was observed in 5 of 6 patients in the highest dose cohorts. In addition, 7 of 16 patients had PSA stable disease with a median duration of 5.6 months.…”

Section: Future Directionsmentioning

confidence: 97%

Current Experience With CTLA4-blocking Monoclonal Antibodies for the Treatment of Solid Tumors

Agarwala¹,

Ribas

2010

Journal of Immunotherapy

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Monoclonal antibodies (mAbs) specific for cytotoxic T lymphocyte-associated antigen 4 (CTLA4) are a novel form of immunotherapy for treatment of patients with advanced cancers. These anti-CTLA4 mAbs prevent normal downregulation of the immune system, thus prolonging and enhancing T-cell activation and potentially promoting an antitumor immune response. Clinical studies in patients with advanced cancers have indicated that CTLA4 blockade with mAbs is associated with antitumor activity in a small percentage of patients and has a manageable toxicity profile. The key limitations for broader applicability of this mode of therapy are better definition of the mechanism that leads to tumor rejection and the validation of favorable observations in single-arm studies into prospectively randomized clinical trials.

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Expanded phase I combination trial of GVAX immunotherapy for prostate cancer and ipilimumab in patients with metastatic hormone-refractory prostate cancer (mHPRC)

Cited by 37 publications

References 0 publications

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

Immune Checkpoint Inhibitor Combinations in Solid Tumors: Opportunities and Challenges

Clonal expansion of CD8 T cells in the systemic circulation precedes development of ipilimumab-induced toxicities

Current Experience With CTLA4-blocking Monoclonal Antibodies for the Treatment of Solid Tumors

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