Renal cancer is the 6th leading cause of cancer death with a survival rate of 11% for stage-IV disease. More than a million skin cancer cases occur each year globally, with a 5-year survival rate of 7 to 9% and a 10-year survival rate of 3 to 6% for stage IV melanoma. These cancers are associated with significant mortality for which survival statistics have remained essentially unchanged for several decades. Past studies have indicated vaccination as a route to boosting anti-tumour T-cell reponses to help kill malignant cells. US investigator Dr Arkadiusz Dudek, from the University of Minnesota, and his team have developed a new method of vaccine-induced augmentation of tumour specific cytotoxic T-lymphocyte responses with the use of latex or silica beads.
The new large multivalent immunogen (LMI) was trialed in 61 patients with renal cancer or malignant melanoma with positive results.
In renal cancer patients, the LMI vaccine was found to prolong time to disease progression to 12.2 months. A significant increase when compared to the standard therapy of renal cancer (high dose interleukin-2) which produced a median progression-free survival of 3.1 months1. Using indicators of median overall survival, patients treated with high dose interleukin-2 survived 17.5 months1 and those treated with the LMI vaccine survived longer than 17.04 months and at current follow up, more than 19 months.
"Our study findings offer hope for patients with metastastic renal cell carcinoma, as this therapy stabilises and controls disease for an average of one year. For patients with metastastic malignant melanoma a large multivalent immunogen vaccine strategy needs to be optimised in order to obtain reproducible results. We hope that by utilising an allogeneic (using human donor cells/tissue) strategy we will observe more frequent and longer lasting responses. This vaccine strategy has no toxicities and treatment is convenient for patients as the vaccine is administered only once a month. In contrast, standard therapeutic strategy using high dose interleukin-2 is very toxic and limited only to selected patients with good performance status, and no cardiac or pulmonary co-morbidities," noted Dr Dudek.
Another immunotherapeutic approach which seeks to boost the responses of effector CD8+ T-cells are DEX vaccines; Dendritic cell derived-EXosomes. In results presented at ECCO, the DEX vaccine, in combination with the alkylating agent cyclophosphamide (CTX), was found to produce antitumour effects superior to that obtained with either the peptide Gp100 plus CTX, or the best DEX vaccination approach currently available in a mouse model of melanoma.
In this new immunotherapeutic approach, CTX acts synergistically with DEX to abolish the function of Treg cells - cells induced by the tumour which suppress the CD8+ responses evoked by DEX. By abrogating the suppressive effect of Treg, CTX maximises the curative effects of DEX vaccination. The success of this combination approach suggests that future therapeutic vaccines aimed at boosting tumour-primed effector T-cells may benefit from procedures that minimise the pro-tumour effects of Treg cells.
About Renal Cancer
Renal cancer is defined as malignancy of the kidney, the organ that is primarily responsible for the removal of metabolic waste products from the body. In 2004, there were just under 40,000 incidents of renal cancer and 22,000 deaths across the EU.
Immunotherapy is the treatment to stimulate or restore the ability of the immune (defense) system to fight infection and disease.
1 McDermott DF, Regan MM, Clark JI, et al. Randomized Phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol 2005;23(1):133-41
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Autologous large multivalent immunogen vaccine for the treatment of stage IV malignant melanoma and stage IV renal cell carcinoma
A. Dudek1, V. Math1, M. Mescher2, J. Miller1
1University of Minnesota, Medicine, Minneapolis, USA
2University of Minnesota, Laboratory Medicine and Pathology, Minneapolis, USA
Renal cell carcinoma is the sixth leading cause of cancer death with a survival rate of 11% for stage IV cancer. More than a million skin cancer cases occur each year globally with a 5 year survival rate of 7-9% and 10 year survival rate of 3-6% for stage IV melanoma. These survival statistics have remained essentially unchanged for several decades. Although immune stimulation with high doses of interleukin-2 has demonstrated efficacy in the treatment of malignant melanoma or renal cell carcinoma, it can be applied only to limited groups of patients. Vaccination has also been explored as a means to boost antitumor T cell responses, which results in the specific killing of malignant cells. We have developed a novel approach of vaccine-induced augmentation of tumor-specific cytotoxic T lymphocyte (CTL) responses using (5-m diameter) latex or silica beads.
61 patients with diagnosis of malignant melanoma or renal cell carcinoma were randomized to the following treatment arms: large multivalent immunogen (LMI) vaccine alone, Cyclophosphamide 300 mg/m2 and LMI vaccine, and Cyclophosphamide 300 mg/m2, LMI vaccine and subcutaneous IL-2 at 1.75 x 106 IU/m2 for 1 week starting on day 5 after LMI vaccine.
No grade 4 toxicities (by NCI CTC v 3.0) were observed in either arm. For patients with malignant melanoma: median and 12 months survival were 8.78 months (95% CI: 7 months, NA) and 46.1% (95% CI: 23.4%, 68.8%), respectively, and median time to disease progression was 2.76 months (95% CI: 1.88, 6.25). For renal cell carcinoma patients: at median follow-up of 12 (range: .4 - 30.4) months overall survival was 75.7% (95% CI: 59.9, 91.4%) and time to disease progression was 12.2 months (95% CI: 6.41 months, NA). One patient with melanoma and one patient with renal cell carcinoma have documented partial response (by RECIST criteria).
LMI vaccine has activity in malignant melanoma as documented by clinical responses and has activity in renal cell carcinoma as measured by prolonged time to disease progression. Phase II study of allogeneic vaccine is now in progress for patients with malignant melanoma to confirm feasibility of LMI strategy in this setting. Phase II study of autologous vaccine in patients with renal cell carcinoma is now in preparation to confirm prolonged time to disease progression observed in this group of patients.
2001 Basic Science
Dendritic cell derived-exosomes boost effector CD8+ T cells in the absence of tumor induced-T regulatory cells : synergistic antitumor effects of cyclophosphamide and exosomes based- vaccines
N. Chaput1, S. Novault1, F. Ghiringhelli1, F. Lemonnier2, A. Carpentier3, J. Taieb1,4
1Inserm Erm0208 Gustave Roussy Institute, Immunology, Villejuif, France
2Pasteur Institute Inserm, Immunology, Paris, France
3Inserm Salpetriere Hospital, Neurology, Paris, France
4Pitie Salpetriere Hospital, Gastroenterology, Paris, France
Dendritic cell derived-exosomes (DEX) are nanomeric antigen presenting vesicles harboring immunogenic MHC/peptides complexes when combined to adjuvants. Since CD4+ CD25+ T regulatory cells (Treg) inhibit the induction of antitumor immunity, we addressed the capacity of Treg to restrict primary and secondary CD8+ T cell responses elicited by DEX in tumor bearing mice. Here we show that DEX combined to the alkylating agent cyclophosphamide (CTX) can mediate peptide dependent-tumor regression of pre-established burdens in HLA-A2.1 transgenic mice bearing B16F10 HLA-A2.1 Gp100 melanoma. These anti-tumor effects are superior to what is observed with peptide Gp100 + CTX and the best DEX vaccination approach currently available DEX+ ODN-CpG (1). NK cell depletion using NK1.1 Ab (PK136), does not abrogate these antitumor effects. However, these antitumor effects were peptide dependant since empty or unrelevant peptide loaded DEX were inefficient, suggesting the crucial role of CD8+ T lymphocytes. Interestingly, CTX abolishes tumor-induced Treg suppressive function and the curative effects of CTX+DEX vaccines are abrogated by the adoptive transfer of Treg. DEX significantly boost expansion and Tc1 differentiation of peptide-induced primary CD8+ T cell responses in the presence of CTX, this effect was not observed using peptide Gp100. The magnitude of secondary T cell immune responses induced by DEX vaccines is subject to control by tumor induced-Treg. Thus, these results imply that therapeutic vaccines aimed at boosting tumor-primed effector T cells could benefit procedures that minimize the effects of Treg.
(1) Chaput et al, JI, 2004