• 7/29/2005
  • Seattle, WA
  • Mary L. Disis
  • Journal of Clinical Oncology, Vol 23, No 22 (August 1), 2005: pp. 4840-4841

The last decade has resulted in the identification of a multitude of tumor-associated antigens and the initiation of clinical trials to determine whether cancer patients can be vaccinated. In this issue of the Journal of Clinical Oncology, Carbone et al1 present an extensive analysis of the immunogenicity and potential clinical efficacy of vaccinating advanced-stage cancer patients against specific K-ras and p53 mutations present in their tumors. This report provides long-term follow-up after vaccination over a period of several years, so the length of time between initiation and publication of the trial allows evaluation of the data in the context of the evolution of more refined methods of vaccination. The authors also present data detailing the pitfalls of the clinical application of targeted therapy, which includes the need to evaluate large numbers of patients to find the few patients who may derive therapeutic benefit. Finally, the authors demonstrate an intriguing association between the development of an antigen-specific immune response and prolonged survival.

The vaccination strategy used in the trial was to incubate mutated K-ras and p53 peptide sequences with peripheral-blood mononuclear cells obtained from each patient. Presumably, antigen-presenting cells present in the peripheral blood would uptake K-ras and p53 peptides, process the peptides, and present the fragments in the context of class I major histocompatibility complex molecules, resulting in the stimulation of antigen-specific cytotoxic CD8+ T cells. It has only been in the last decade that clinical trials of cancer vaccines have been able to demonstrate any reproducible and detectable antigen-specific immunity resulting from such immunizations.2 As in the initial studies of this approach, Carbone et al1 describe low to moderate peptide-specific T-cell immunity developing in a minority of patients. Subsequent to the initiation of this trial, more potent antigen-presenting cells have been identified, such as dendritic cells.3 Over the last several years, methods have been developed to purify dendritic cells from the peripheral blood and to use them clinically to present tumor antigens to T cells. Methods continue to evolve to optimize the efficacy of dendritic cell vaccines.4 Potentially, the use of such professional antigen-presenting cells could increase the number of patients able to develop immune responses after vaccination. The authors also describe the lack of immunogenicity of vaccination in patients with rapidly progressing diseases such as pancreatic cancer. Findings such as this have resulted in a re-evaluation of the clinical application of cancer vaccines. Most cancer vaccine trials now focus on immunization in the adjuvant setting, aiming to prevent cancer relapse rather than to treat measurable disease. Even the most potent infectious disease vaccines are generally not used for treating established infections; likewise, cancer vaccines may have greatest benefit in the management of micrometastatic disease or even in the prevention of cancer in high-risk populations.

The explosion in the identification of tumor antigens was fueled by advances in molecular technology and immunology. Similarly, the identification of molecular targets that affect growth pathways in cancer has resulted in the generation of novel and promising cancer therapies.5 Data presented by Carbone et al1 underscore the need to develop rapid and inexpensive methods to screen patients for genetic alterations that may predict clinical efficacy of novel reagents. The authors evaluated nearly 300 patients to find the 14% of individuals whose tumors contained the appropriate mutations and were eligible for enrollment by clinical criteria. Recent studies with other forms of targeted cancer therapy, such as gefitinib in the treatment of lung cancer,6 highlight the need to choose patients most likely to respond to intervention, as Carbone et al1 did in this clinical trial. It is frustrating to refer patients for screening for such trials only to find out that they are ineligible for a particular therapy. However, studies such as this demonstrate that there is a need for persistence to define the utility of a promising approach. Hopefully, more rapid clinical successes resulting from early-stage studies enrolling only the most appropriate patient populations will facilitate the entry of novel agents into clinical practice.

The most provocative aspect of the trial is the association of a specific type of immune response with prolonged survival. The authors describe the identification of peptide-specific cytotoxic T cells and interferon gamma secretion, but not interleukin-5 secretion, as favorable prognostic markers. Both K-ras and p53 are proteins expressed within the cell and not on the surface of the cell. Intracellular proteins are generally processed and presented in major histocompatibility complex class I molecules, which represent the pathway for stimulating a cytotoxic T-cell response. T cells that elaborate interferon gamma support the proliferation of cytotoxic T cells. Interleukin-5 secretion does not. Therefore, the data suggest that the generation of peptide-specific cytotoxic T cells may impact tumor progression. Phase II trials focused on clinical outcome will help define the utility of mutated K-ras and p53 peptide-based vaccines in the treatment of cancer patients.

Cancer treatment may evolve to combined-modality regimens that initially use standard cytotoxic agents to debulk disease, followed by targeted approaches. One may imagine a future where K-ras–driven tumor growth is halted by a specific inhibitor and then K-ras mutation–containing tumor cells are eradicated by mutation-specific cytotoxic T cells. Hopefully soon, cancer growth pathways will be silenced via multiple targeted mechanisms.

Author’s affiliation:

University of Washington, Fred Hutchinson Cancer Research Center, Seattle, WA

References:

(1)Carbone DP, Ciernik IF, Kelley MJ, et al: Immunization with mutant p53- and K-ras–derived peptides in cancer patients: Immune response and clinical outcome. J Clin Oncol 23: 5099-5107, 2005

(2)Gjertsen MK, Bakka A, Breivik J, et al: Vaccination with mutant ras peptides and induction of T-cell responsiveness in pancreatic carcinoma patients carrying the corresponding RAS mutation. Lancet 346: 1399-1400, 1995

(3)Banchereau J, Steinman RM: Dendritic cells and the control of immunity. Nature 392: 245-252, 1998

(4)Steinman RM, Pope M: Exploiting dendritic cells to improve vaccine efficacy. J Clin Invest 109: 1519-1526, 2002[Free Full Text]
Sawyers C: Targeted cancer therapy. Nature 432: 294-297, 2004

(5)Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304: 1497-1500, 2004