Tumor Heterogeneity as a Rationale for a Multi-epitope Approach in an Autologous Renal Cell Cancer Tumor Vaccine
the ONA take:
A heterogeneic mixture of different tumor-associated antigens and danger signals is present in renal cell carcinomas (RCCs) and at least 1 tumor-associated antigen and 1 danger protein is needed to induce an immune response with an autologous RCC tumor vaccine, a study published in the journal OncoTargets and Therapy has shown.
For the study, researchers sought to characterize a panel of 36 tumor-associated antigens and cellular marker proteins from tumor material of 133 patients with RCC who underwent radical neprhectomy. To do this, the investigators used ELISA assays, Western blots, and topological proteomics. Mice were immunized to observe the induction of tumor-associated antigen-specific antibodies.
Results showed that tumor heterogeneity was present, meaning the tumor cells within a single tumor were highly diverse. However, gene and antigen patterns between tumors were inconsistent. These findings suggest that a multi-epitope approach is necessary for the creation of a successful immunotherapy in RCC.
Furthermore, when mice were given the autologous RCC vaccine, researchers found that at least 1 antigen and 1 danger signal, such as heat shock proteins, is required for the induction of an immune response. This may indicate that that is a minimal requirement for an autologous or artificially created tumor vaccine.
OncoTargets and Therapy
Purpose: An autologous tumor vaccine already used successfully in the immune therapy of renal cell carcinoma was investigated in detail. The evaluation of potential tumor markers should allow for the assessment of potency according to pharmaceutical regulations.
Methods: A panel of 36 tumor-associated antigens and cellular marker proteins was characterized in a total of 133 tumor cell lysates by methods such as ELISA, Western blots, and topological proteomics. The induction of tumor-associated antigen-specific antibodies was demonstrated by immunization in mice.
Results: Tumor heterogeneity was demonstrated: none of the tumor-associated antigens investigated were detectable in each tumor lysate. In parallel, the coincidental presence of potential danger signals was shown for HSP-60 and HSP-70. The presence of both antigen and danger signal allowed a successful induction of an immune response in a murine model.
Conclusion: The verified tumor heterogeneity indicates the need for a multi-epitope approach for the successful immunotherapy in renal cell carcinoma.
Keywords: renal cell carcinoma, kidney cancer, tumor-associated antigens, tumor marker, ELISA, Western Blot, immunotherapy, therapeutic vaccine, potency testing, topological proteomics
Renal cell carcinoma is an orphan disease with an incidence of less than 1.6:10.000.1 Only about 3% of all malignant tumors in adults develop in the kidney and 85% of these tumors are identified as renal clear cell carcinoma (RCC). Most cases are discovered incidentally and 25%–30% are already in a metastatic stage. The median age of patients at primary diagnosis is 60 years and the male to female ratio is 3:2.
Standard therapy of organ-confined and locally advanced RCC is partial or radical nephrectomy, whereas patients with distant metastasis are often treated with nonspecific immunotherapy or, more recently, with targeted therapy.2–4 The 5-year relative survival rate for patients diagnosed with RCC between 1996 and 2002 was 65.6% in the US compared to 68.5% in Germany (diagnosis between 2000 and 2002).5
After radical nephrectomy, despite the significant stage-related risk of tumor progression, no effective adjuvant treatment without major side effects is currently approved. Drugs that show some efficacy in patients with metastatic RCC such as interferon-α and interleukin-2 (IL-2) failed to demonstrate a benefit in the adjuvant setting.6–8 Until now, only a 1997 initiated prospective randomized Phase III trial showed a significant effect in overall survival after radical nephrectomy accompanied by treatment with an autologous renal tumor cell vaccine.8 Furthermore, by comparing data from a compassionate use program with a historical group of patients observed for more than 10 years and treated by radical nephrectomy, May et al10 demonstrated the same significant effect on the overall survival (42.3 months) for T3 tumors.
In addition, discussions on common tumor markers or tumor-associated antigens (TAA) as potential targets for immunotherapy are ongoing especially since authorities like the European Medical Agency (EMA) and the US Food and Drug Administration request additional information about the potency and potential risks of these autologous applied antigens.11,12 The potential risk might be the induction of an autoimmune disease. In this context, Zinkernagel (personal communication, 2008) defined any immunological antitumor reaction as autoimmune that has to be differentiated from an autoimmune disease.