IMA901: a multi-peptide cancer vaccine for treatment of renal cell cancer (original) (raw)
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IMA901 for metastatic renal cell carcinoma in the context of new approaches to immunotherapy
Future oncology (London, England), 2014
The promising option of immunotherapy for metastatic renal cell carcinoma has evolved from rather unspecific approaches to a specific activation of an anti-tumor T-cell response. The latest step is a synthetic peptide vaccine called IMA901, which demonstrated a clear association between a provoked T-cell response and a prolonged overall survival. The results of IMA901 for the treatment of metastatic renal cell carcinoma are discussed together with new approaches to immunotherapy, such as local and systemic immunomodulation with adjuvants, checkpoint inhibitors, classical chemotherapeutics, such as cyclophosphamide or tyrosine kinase inhibitors. The capability of theses substances to modulate leukocytes subsets, such as myeloid-derived suppressor cells, Tregs or Th17 cells, are outlined together with the possibility to combine them with tumor vaccination strategies to achieve a higher cancer specificity and immunogenicity.
Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang
Clinical Cancer Research, 2007
In patients with progressive malignancy, the natural balance between proinflammatory (Yang) and inhibitory (regulatory or Yin) immune pathways is disrupted and favors cancer-specific immune suppression. Therapy with interleukin 2 (IL-2) can mobilize immune effector cells that recognize and destroy cancer. High-dose IL-2 is the only therapy that has consistently induced complete durable remissions in patients with metastatic renal cell carcinoma (RCC) but only in a few of them. The lack of benefit in most metastatic RCC patients is likely due to the ineffective manipulation of other immune circuits critical in regulating tumor cytotoxic pathways. The limited clinical activity of IL-2, RCC vaccines, and other immune therapies to date leads us to postulate that effective clinical treatment strategies will need to simultaneously enhance proinflammatory pathways and disrupt regulatory pathways. We present preliminary studies in RCC patients to highlight the complexity of the regulatory pathways and our approach to shifting the balance of proinflammatory and regulatory immune pathways using dendritic cell^tumor lysate vaccine followed by cytokine therapy.
Update on vaccine development for renal cell cancer
Open Access Journal of …, 2010
Renal cell carcinoma (RCC) remains a significant health concern that frequently presents as metastatic disease at the time of initial diagnosis. Current first-line therapeutics for the advanced-stage RCC include antiangiogenic drugs that have yielded high rates of objective clinical response; however, these tend to be transient in nature, with many patients becoming refractory to chronic treatment with these agents. Adjuvant immunotherapies remain viable candidates to sustain disease-free and overall patient survival. In particular, vaccines designed to optimize the activation, maintenance, and recruitment of specific immunity within or into the tumor site continue to evolve. Based on the integration of increasingly refined immunomonitoring systems in both translational models and clinical trials, allowing for the improved understanding of treatment mechanism(s) of action, further refined (combinational) vaccine protocols are currently being developed and evaluated. This review provides a brief history of RCC vaccine development, discusses the successes and limitations in such approaches, and provides a rationale for developing combinational vaccine approaches that may provide improved clinical benefits to patients with RCC.
Gene Therapy, 2011
Despite novel targeted agents, prognosis of metastatic renal cell cancer (RCC) remains poor, and experimental therapeutic strategies are warranted. Transfection of tumor cells with co-stimulatory molecules and/or cytokines is able to increase immunogenicity. Therefore, in our clinical study, 10 human leukocyte antigen (HLA)-A*0201 + patients with histologicallyconfirmed progressive metastatic clear cell RCC were immunized repetitively over 22 weeks with 2.5-40Â10 6 interleukin (IL)-7/CD80 cotransfected allogeneic HLA-A*0201 + tumor cells (RCC26/IL-7/CD80). Endpoints of the study were feasibility, safety, immunological and clinical responses. Vaccination was feasible and safe. In all, 50% of the patients showed stable disease throughout the study; the median time to progression was 18 weeks. However, vaccination with allogeneic RCC26/IL-7/ CD80 tumor cells was not able to induce TH1-polarized immune responses. A TH2 cytokine profile with increasing amounts of antigen-specific IL-10 secretion was observed in most of the responding patients. Interferon-g secretion by patient lymphocytes upon antigen-specific and non-specific stimulation was substantially impaired, both before and during vaccination, as compared with healthy controls. This is possibly due to profound tumor-induced immunosuppression, which may prevent induction of antitumor immune responses by the gene-modified vaccine. Vaccination in minimal residual disease with concurrent depletion of regulatory cells might be one strategy to overcome this limitation.
Nature Medicine, 2012
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.
Vaccines in Renal Cell Carcinoma
Seminars in Oncology, 2006
Considerable progress in our understanding of the molecular and cellular events that promote growth and progression of renal cell carcinoma (RCC) has dramatically improved the prospects of significantly altering the progression and metastatic potential of renal neoplasms. Cancer vaccination, one form of active specific immunotherapy, represents a promising approach which aims to expand the number of T cells capable of reducing/ eradicating the tumor mass, and to induce tumor-specific memory T cells that control tumor recurrence. Over the past decade, a number of vaccine strategies have moved from the bench to the bedside and have now become subject to rigorous clinical investigation. This review will examine the current status of vaccine-based therapy for advanced RCC, discuss their mechanisms of action, and provide information on relevant clinical trials. Also discussed are future applications that seek to enhance the vaccine-mediated T-cell response or to make vaccines applicable to broader patient cohorts.
Role of immunotherapy for renal cell cancer in 2011
Journal of the National Comprehensive Cancer Network : JNCCN, 2011
High-dose interleukin-2 (IL-2) and interferon were the most commonly administered therapies before the recent introduction of targeted agents, including vascular endothelial growth factor and mammalian target of rapamycin pathway inhibitors. Although the new agents result in a progression-free survival benefit, high-dose IL-2 remains the only agent with proven efficacy in producing durable complete and partial responses in patients with metastatic renal cell carcinoma (RCC). Furthermore, although the use of single-agent interferon has decreased significantly since the introduction of targeted therapy, it remains in the frontline setting in combination with bevacizumab as a result of 2 large phase III trials. Lastly, improved understanding of immune regulation has led to the advancement of targeted immunotherapy using immune checkpoint inhibitors that have shown promising activity and are moving forward in clinical development. This article focuses on the current status of immunother...
Immunotherapy for metastatic renal cell carcinoma
The Cochrane library, 2017
Background Since the mid-2000s, the field of metastatic renal cell carcinoma (mRCC) has experienced a paradigm shift from non-specific therapy with broad-acting cytokines to specific regimens, which directly target the cancer, the tumour microenvironment, or both. Current guidelines recommend targeted therapies with agents such as sunitinib, pazopanib or temsirolimus (for people with poor prognosis) as the standard of care for first-line treatment of people with mRCC and mention non-specific cytokines as an alternative option for selected patients. In November 2015, nivolumab, a checkpoint inhibitor directed against programmed death-1 (PD-1), was approved as the first specific immunotherapeutic agent as second-line therapy in previously treated mRCC patients. Objectives To assess the effects of immunotherapies either alone or in combination with standard targeted therapies for the treatment of metastatic renal cell carcinoma and their efficacy to maximize patient benefit. Search methods We searched the Cochrane Library, MEDLINE (Ovid), Embase (Ovid), ISI Web of Science and registers of ongoing clinical trials in November 2016 without language restrictions. We scanned reference lists and contacted experts in the field to obtain further information. Selection criteria We included randomized controlled trials (RCTs) and quasi-RCTs with or without blinding involving people with mRCC.