IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial

Rini, Brian I.; Stenzl, Arnulf; Zdrojowy, R.; Kogan, M. I.; Школьник, М. И.; Oudard, Stéphane; Weikert, Steffen; Bracarda, Sergio; Crabb, Simon J.; Bedke, Jens; Ludwig, Joerg; Maurer, Dominik; Mendrzyk, Regina; Wagner, Claudia; Mahr, Andrea; Fritsche, Jens; Weinschenk, Toni; Walter, Steffen; Kirner, Alexandra; Singh‐Jasuja, Harpreet; Reinhardt, Carsten; Eisen, Tim

doi:10.1016/s1470-2045(16)30408-9

Cited by 183 publications

(126 citation statements)

References 17 publications

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“…RCC is been considered an immunogenic tumor and therapy with cytokines such as IL2 and IFNa has been used although the responses have been mild and associated with toxicity. Long-term responses and complete remissions have been occasionally observed in mRCC patients treated with immunotherapy (27,28). The induction of an immune response such as the one elicited by the multi-peptide IMA901 vaccine was associated with a clinical benefit.…”

Section: Immune Profile Of Mrcc Patients During Tki Treatmentmentioning

confidence: 99%

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Zizzari

Napoletano

Botticelli

et al. 2018

Cancer Immunology Research

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Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/b-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4 þ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711-22. Ó2018 AACR.

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Section: Immune Profile Of Mrcc Patients During Tki Treatmentmentioning

confidence: 99%

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Zizzari

Napoletano

Botticelli

et al. 2018

Cancer Immunology Research

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“…Based on article identification and selection, we totally included 28 trials from 35 articles (9-30), involving 17,466 randomly assigned patients ( Figure 1) (31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42)(43).…”

Section: Trial Searching and Characteristicsmentioning

confidence: 99%

Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

Zhang¹,

Zhang²,

Tang³

et al. 2017

Ann. Transl. Med.

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“…However, in this carefully designed randomized multi-center study IMA901 did not prolong overall survival in the IMA901 co-treated patient cohort. 48 …”

Section: Introductionmentioning

confidence: 99%

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

et al. 2018

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Mutated proteins arising from somatic mutations in tumors are promising targets for cancer immunotherapy. They represent true tumor-specific antigens (TSAs) as they are exclusively expressed in tumors, reduce the risk of autoimmunity and are more likely to overcome tolerance compared to wild-type (wt) sequences. Hence, we designed a panel of long peptides (LPs, 28–35 aa) comprising driver gene mutations in TP35 and KRAS frequently found in gastrointestinal tumors to test their combined immunotherapeutic potential. We found increased numbers of T cells responsive against respective mutated and wt peptides in colorectal cancer patients that carry the tested mutations in their tumors than patients with other mutations. Further, active immunization of HLA(-A2/DR1)-humanized mice with mixes of the same mutated LPs yielded simultaneous, polyvalent CD8+/CD4+ T cell responses against the majority of peptides. Peptide-specific T cells possessed a multifunctional cytokine profile with CD4+ T cells showing a TH1-like phenotype. Two mutated peptides (Kras[G12V], p53[R248W]) induced significantly higher T cell responses than corresponding wt sequences and comprised HLA-A2/DR1-restricted mutated epitopes. However, vaccination with the same highly immunogenic LPs strongly increased systemic regulatory T cells (Treg) numbers in a syngeneic sarcoma model over-expressing these mutated protein variants and resulted in accelerated tumor outgrowth. In contrast, tumor outgrowth was delayed when vaccination was directed against tumor-intrinsic Kras/Tp53 mutations of lower immunogenicity. Conclusively, we show that LP vaccination targeting multiple mutated TSAs elicits polyvalent, multifunctional, and mutation-specific effector T cells capable of targeting tumors. However, the success of this therapeutic approach can be hampered by vaccination-induced, TSA-specific Tregs.

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IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial

Abstract: Immatics Biotechnologies.

Cited by 183 publications

References 17 publications

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

TK Inhibitor Pazopanib Primes DCs by Downregulation of the β-Catenin Pathway

Evaluation bias in objective response rate and disease control rate between blinded independent central review and local assessment: a study-level pooled analysis of phase III randomized control trials in the past seven years

Long-peptide vaccination with driver gene mutations in p53 and Kras induces cancer mutation-specific effector as well as regulatory T cell responses

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