Download Editorial Comment on: Vaccine Therapy in Patients with Renal Cell

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come of a clinical phase I/II trial in patients with metastatic renal cell carcinoma. Hum Gene Ther 2003;14:483–
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cell vaccines. J Clin Immunol 2004;24:86–96.
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Editorial Comment on: Vaccine Therapy in
Patients with Renal Cell Carcinoma
Joaquim Bellmunt
University Hospital del Mar, Barcelona, Spain
[email protected]
Antoni Ribas
University of California Los Angeles (UCLA),
Los Angeles, CA, USA
[email protected]
[44] Wei YC, Sticca RP, Li J, et al. Combined treatment
of dendritoma vaccine and low-dose interleukin-2
in stage IV renal cell carcinoma patients induced
clinical response: a pilot study. Oncol Rep 2007;18:
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[45] Uemura H, Fujimoto K, Tanaka M, et al. A phase I trial of
vaccination of CA9-derived peptides for HLA-A24-positive
patients with cytokine-refractory metastatic renal cell
carcinoma. Clin Cancer Res 2006;12:1768–75.
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peptide immunotherapy for renal cell carcinoma. Microbiol Immunol 2007;51:519–30.
[47] Suekane S, Nishitani M, Noguchi M, et al. Phase I trial of
personalized peptide vaccination for cytokine-refractory
metastatic renal cell carcinoma patients. Cancer Sci
2007;98:1965–8.
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preparation of Mycobacterium vaccae (SRL172) as an
immunotherapeutic agent in renal cancer. Eur J Cancer
2008;44:216–23.
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autologous therapeutic vaccine (HSPPC-96; vitespen) versus observation alone for patients at high risk of recurrence after nephrectomy for renal cell carcinoma: a
multicentre, open-label, randomised phase III trial. Lancet 2008;372:145–54.
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tumour-derived vitespen vaccine: clinical findings. Br J
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Immunother 2007;30:825–30.
Immune-stimulating approaches have resulted
in low but reproducible response rates in patients
with metastatic renal cell carcinoma (RCC). A key
feature of these responses is that they are
frequently durable, providing a rare chance of cure
in small subsets of patients, which led to the
approval of high-dose interleukin 2 (IL-2) by the US
Food and Drug Administration. Newer generations
of immune-stimulating and vaccine platforms
have been tested to avoid the high toxicity of IL-2.
european urology 55 (2009) 1333–1344
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In RCC, a limited number of tumor associated
antigens have been identified, which has led to the
testing of cell–based tumor vaccines. Approaches
have included gene-modified tumor cells and
dendritic cell–based vaccines [1]. Most of these
approaches, however, failed to demonstrate significant efficacy in randomized phase 3 trials. The
single exception was Reniale, a patient-specific
vaccine using lysates from autologous tumors cells
extracted at the time of surgery. Although promising results were reported with Reniale, questions
arose regarding the study design [2]. There are
plans to conduct an international phase 3 trial to
confirm these results, which will hopefully lead to
regulatory approval for the product.
As Van Poppel et al [3] describe in their review
article, there have been a number of phase 3
clinical trial failures in the field of RCC. What
explains these failures [4,5]?
Some vaccines (eg, Oncophage) may have low
potency to induce specific T-cell responses, resulting in controlling patients with only small-volume
disease. The pivotal clinical trial of Oncophage
showed improvement in the unplanned analysis of
earlier stage patients but not in the overall patient
population.
Other vaccines (like Trovax) use single-cancer
antigens that may facilitate treatment escape
through downregulation or total expression loss.
Additionally, in the Trovax trial, problems in the
design, like the use of adjuvant alone in the control
arm, could also have skewed the statistical power.
Finally, the development decisions of a vaccine
program need to be based on clinical data, not just
on immune response (eg, with Vitespen, for which
rare objective regressions of metastatic disease
were seen). Immune responses have not been
predictive of clinical benefit. The rare vaccines that
do generate brisk B-cell or T-cell responses, for
example, apparently do not induce the correct
effector functions to reject tumors or to overcome
immunosuppression.
As stated by Van Poppel et al [3], the success of
clinical effectiveness in selected populations combined with more potent vaccines with novel
adjuvants and strategies aimed at circumventing
tumor-associated immunosuppression [4] may
improve the efficacy of tumor vaccines and cellular
immunotherapy so that they live up to their
promise.
Editorial Comment on: Vaccine Therapy in
Patients with Renal Cell Carcinoma
Peter E. Clark
Vanderbilt University Medical Center, A-1302 Medical
Center North, Nashville, TN 37232-2765 USA
[email protected]
including tyrosine kinase inhibitors such as sutent
and sorafenib, mammalian target of rapamycin
(mTOR) inhibitors such as temsirolimus, and
vascular endothelial growth factor (VEGF) inhibitors such as bevacizumab. With all of these
options, one might legitimately ask, why bring
up another treatment approach such as vaccine
therapy?
The truth is that neither the older immunomodulatory approaches nor the more recent targeted
therapies frequently cure patients with advanced
RCC. To be sure, the targeted therapies are a major
advance and have changed the way this disease is
managed, but there is still plenty of room for
The range of options available for treating
advanced renal cell carcinoma (RCC) has expanded
tremendously in the last several years. It was not
that long ago that the only options available were
immunomodulatory approaches such as high dose
interleukin 2 or interferon-a. The menu has now
expanded with a variety of targeted therapies,
References
[1] Rescigno M, Avogadri F, Curigliano G. Challenges and
prospects of immunotherapy as cancer treatment. Biochim Biophys Acta 2007;1776:108–23.
[2] Kommu S. Renal-cell carcinoma: vaccination and risk of
tumour progression. Lancet 2004;363:1557, author reply
1557.
[3] Van Poppel H, Joniau S, Van Gool SW. Vaccine therapy in
patients with renal cell carcinoma. Eur Urol 2009;55:
1333–44.
[4] Begley J, Ribas A. Targeted therapies to improve tumor
immunotherapy. Clin Cancer Res 2008;14:4385–91.
[5] Johnson RS, Walker AI, Ward SJ. Cancer vaccines: will we
ever learn? Expert Rev Anticancer Ther 2009;9:67–74.
DOI: 10.1016/j.eururo.2009.01.044
DOI of original article: 10.1016/j.eururo.2009.01.043