Immunogenicity and Antitumor Effects of Vaccination with Peptide Vaccine +/− Granulocyte-Monocyte Colony-Stimulating Factor and/or IFN-α2b in Advanced Metastatic Melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696

Kirkwood, John M.; Lee, Sandra; Moschos, Stergios J.; Albertini, Mark R.; Michalak, John C.; Sander, Cindy; Whiteside, Theresa L.; Butterfield, Lisa H.; Weiner, Louis M.

doi:10.1158/1078-0432.ccr-08-1231

Cited by 131 publications

(112 citation statements)

References 39 publications

(52 reference statements)

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“…Although there have been numerous peptide vaccine studies, our study has similarities to a few and is unique from many others. Similar to our study, mixtures of antigenic peptides derived from a few proteins with various HLA-binding affinities have been reported to induce individual peptide-specific and tumor-specific T-cell responses in ovarian and melanoma patients (31)(32)(33). In these studies, different HLA-specific peptides derived from a small group of proteins that are not involved in critical tumor pathways (e.g., cancer testis antigens that do not play any role in tumorigenesis and survival) were mixed.…”

Section: Discussionsupporting

confidence: 86%

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MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer

Morse

Secord

Blackwell

et al. 2011

Clinical Cancer Research

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Purpose: The purpose of this study is to test whether peptide epitopes chosen from among those naturally processed and overpresented within MHC molecules by malignant, but not normal cells, when formulated into cancer vaccines, could activate antitumor T-cell responses in humans.Experimental Design: Mixtures of human leukocyte antigen A2 (HLA-A2)-binding ovarian cancerassociated peptides were used to activate naive T cells to generate antigen-specific T cells that could recognize ovarian and breast cancers in vitro. Combinations of these peptides (0.3 mg of each peptide or 1 mg of each peptide) were formulated into vaccines in conjunction with Montanide ISA-51 and granulocyte monocyte colony stimulating factor which were used to vaccinate patients with ovarian and breast cancer without evidence of clinical disease in parallel pilot clinical trials.Results: T cells specific for individual peptides could be generated in vitro by using mixtures of peptides, and these T cells recognized ovarian and breast cancers but not nonmalignant cells. Patient vaccinations were well tolerated with the exception of local erythema and induration at the injection site. Nine of the 14 vaccinated patients responded immunologically to their vaccine by inducing peptide-specific T-cell responses that were capable of recognizing HLA-matched breast and ovarian cancer cells.Conclusion: Mixtures of specific peptides identified as naturally presented on cancer cells and capable of activating tumor-specific T cells in vitro also initiate or augment immune responses toward solid tumors in cancer patients.

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Section: Discussionsupporting

confidence: 86%

“…We used GM-CSF at 100 mg per injection and believe the GM-CSF was likely immunostimulatory at this dose. Regarding our use of a weekly schedule (with a 1-week break in the middle), the best immunization schedule is unclear with some studies by using weekly or biweekly followed by monthly (28)(29)(30)(31)(32)(33)(34)(35)(36)(37).…”

Section: Discussionmentioning

confidence: 99%

MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer

Morse

Secord

Blackwell

et al. 2011

Clinical Cancer Research

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“…(iii) The empirical threshold for detection of a vaccine-induced response was set to a conservative value (4× above baseline), as the in vitro culture is expected to be associated with a resulting lower precision as compared with an ex vivo assay. (iv) In several reported immunotherapy studies [60][61][62][63][64] , ex vivo detectable, vaccineinduced T cell responses in patients with melanoma were readily detected. It is worth noting that in these studies, altered ligands or the HLA-A*02-restricted Melan-A peptide were almost exclusively used.…”

Section: Identification and Gene Expression Analysis Of Hla-restrictementioning

confidence: 99%

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Walter

Weinschenk

Stenzl

et al. 2012

Nat Med

705

596

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1 2 5 4 VOLUME 18 | NUMBER 8 | AUGUST 2012 nAture medicine Therapeutic cancer vaccines hold the promise of combining meaningful efficacy (prolongation of survival) with very good safety and tolerability, as has been shown in several recent randomized trials 1-3 . However, development of cancer vaccines remains a major challenge, with little knowledge of (i) the optimal tumor antigens to target, (ii) suitable agents to counteract regulatory mechanisms opposing successful immunotherapy and (iii) surrogate and predictive biomarkers that can improve our understanding of these regulatory mechanisms and predict a patient's response to therapy. The first major issue addressed in this work is whether relevant HLArestricted peptides for immunotherapeutic intervention in patients with RCC can be identified and clinically validated. We defined the relevance of the antigens as their natural presence on the tumor in the majority of RCC samples, their immunogenicity (induction of T cell responses in clinical studies) and the association of the vaccine-induced T cell responses with clinical benefit. For the identification, selection and preclinical immunological validation of such antigens, we used the antigen discovery platform XPRESIDENT 4,5 to create a multipeptide vaccine designated IMA901 for immunotherapy of RCC. We tested IMA901 in HLA-A*02 + subjects with advanced RCC in two clinical trials, a phase 1 (n = 28) and a randomized phase 2 (n = 68) trial, both of which assessed the association of T cell responses to IMA901 with clinical benefit.

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“…4). Early in their development, these strategies worked in only a small percentage of patients, with objective responses in most studies around 10% (5,6). Although progress has been made in identifying markers that will prospectively select those patients who will benefit most (7), it is desirable to understand the reasons these therapies are not more broadly active and to develop additional immune modulating agents.…”

Section: Introductionmentioning

confidence: 99%

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

Koblish

Hansbury

Bowman

et al. 2010

Molecular Cancer Therapeutics

228

190

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Malignant tumors arise, in part, because the immune system does not adequately recognize and destroy them. Expression of indoleamine-2,3-dioxygenase (IDO; IDO1), a rate-limiting enzyme in the catabolism of tryptophan into kynurenine, contributes to this immune evasion. Here we describe the effects of systemic IDO inhibition using orally active hydroxyamidine small molecule inhibitors. A single dose of INCB023843 or INCB024360 results in efficient and durable suppression of Ido1 activity in the plasma of treated mice and dogs, the former to levels seen in Ido1-deficient mice. Hydroxyamidines potently suppress tryptophan metabolism in vitro in CT26 colon carcinoma and PAN02 pancreatic carcinoma cells and in vivo in tumors and their draining lymph nodes. Repeated administration of these IDO1 inhibitors impedes tumor growth in a dose-and lymphocyte-dependent fashion and is well tolerated in efficacy and preclinical toxicology studies. Substantiating the fundamental role of tumor cell-derived IDO expression, hydroxyamidines control the growth of IDO-expressing tumors in Ido1-deficient mice. These activities can be attributed, at least partially, to the increased immunoreactivity of lymphocytes found in tumors and their draining lymph nodes and to the reduction in tumor-associated regulatory T cells. INCB024360, a potent IDO1 inhibitor with desirable pharmaceutical properties, is poised to start clinical trials in cancer patients. Mol Cancer Ther; 9(2); 489-98.

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Immunogenicity and Antitumor Effects of Vaccination with Peptide Vaccine +/− Granulocyte-Monocyte Colony-Stimulating Factor and/or IFN-α2b in Advanced Metastatic Melanoma: Eastern Cooperative Oncology Group Phase II Trial E1696

Cited by 131 publications

References 39 publications

MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer

MHC Class I–Presented Tumor Antigens Identified in Ovarian Cancer by Immunoproteomic Analysis Are Targets for T-Cell Responses against Breast and Ovarian Cancer

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Hydroxyamidine Inhibitors of Indoleamine-2,3-dioxygenase Potently Suppress Systemic Tryptophan Catabolism and the Growth of IDO-Expressing Tumors

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