Vaccination of Patients With Metastatic Renal Cancer With Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Interferon-α

Abstract

Approximately 90% of renal cell tumors overexpress the tumor antigen 5T4. The attenuated strain of vaccinia virus, modified vaccinia Ankara, has been engineered to express 5T4 (TroVax). We conducted an open-label phase 1/2 trial in which TroVax was administered alongside interferon-alpha (IFNalpha) to 11 patients with metastatic renal cell carcinoma. Antigen-specific cellular and humoral responses were monitored throughout the study, and clinical responses were assessed by measuring the changes in tumor burden by computed tomography scan (Response Evaluation Criteria In Solid Tumors). The primary objective was to assess the safety, immunogenicity, and efficacy of TroVax when given alongside IFNalpha. Treatment with TroVax plus IFNalpha was well tolerated with no serious adverse events attributed to TroVax. All 11 patients mounted 5T4-specific antibody responses and 5 (45%) mounted cellular responses. No objective tumor responses were seen, but the overall median time to progression (TTP) of 9 months (range: 2.1 to 26+ mo) was longer than expected for IFNalpha alone. For the 10 clear cell patients the TTP ranged from 3.9 to 26+ months, with a median TTP of 10.4 months. The high frequency of 5T4-specific immune responses and prolonged median TTP for clear cell patients compared with that expected for IFNalpha alone is encouraging and warrants further investigation.

Vaccination of Metastatic Renal Cancer Patients with MVA-5T4: A Randomized, Double-Blind, Placebo-Controlled Phase III Study

“…Results from phase I and II clinical studies of MVA-5T4 in renal, colorectal, and prostate cancer patients were encouraging and showed that immune responses were induced in almost all treated patients, and associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16). In particular, studies in RCC and colorectal cancer patients have detected an association between 5T4-specific (but not MVA) antibody responses and enhanced survival (9,12,16).…”

“…These studies showed MVA-5T4 to be well tolerated and able to induce 5T4-specific immune responses in most patients. Furthermore, associations between 5T4-specific cellular or humoral responses and clinical benefit were reported in seven of the nine studies (8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Interferon-α Suppresses cAMP to Disarm Human Regulatory T Cells

“…In line with this assertion, IFN-a treatment has been previously observed to reduce Treg numbers in patients with melanoma or renal cell carcinoma (37,38), whereas, conversely, declining IFN-a levels and impaired IFN-a signaling in patients with cancer seem to be correlated with an increase in the number of Treg and a higher risk of cancer progression (39)(40)(41). Recent reports on improved immune responses upon co-administration of IFN-a with peptide vaccines in renal (42), pancreatic (43), and colorectal cancer (44) represent additional evidence. Numerous investigations have firmly established a key role of cAMP in the suppressive function of Treg (27)(28)(29)(30)(45)(46)(47).…”

Vaccine and Cancer Therapy for Genitourinary Tumors

“…Treatment was well tolerated with no serious adverse events, and all patients demonstrated 5T4-specific antibody response. Overall median time to progression was longer than interferon-alpha when administered alone (Hawkins, Macdermott, Shablak, et al, 2009). …”