HPV16/18 E7-pulsed dendritic cell vaccination in cervical cancer patients with recurrent disease refractory to standard treatment modalities.
OBJECTIVE
To evaluate the potential of human papillomavirus (HPV) type 16 and 18 E7 antigen-loaded autologous dendritic cells (DC) as a therapeutic cellular vaccine in a case series of cervical cancer patients harboring recurrent/metastatic disease refractory to standard treatment modalities.


METHODS
Autologous monocyte-derived DC were pulsed with recombinant HPV16 E7 or HPV18 E7 oncoproteins and administered to 4 cervical cancer patients. Vaccinations were followed by subcutaneous administration twice daily of low doses of human recombinant interleukin-2 (1 x 10(6) IU/m2) from day 3 to day 7. Safety, toxicity, delayed type hypersensitivity reactions (DTH), clinical responses, and induction of serological and cellular immunity against HPV16/18 E7 were monitored.


RESULTS
The vaccine was well-tolerated in all patients and no local or systemic side effects or toxicity were recorded. Three out of four patients were found to be significantly immunocompromised before starting the vaccination treatment, as assessed by DTH with a panel of recall antigens. Specific humoral and cellular CD4+ T cell responses to the E7 vaccine were detected in 2 patients, as detected by ELISA and by IFN-gamma ELISpot assays, respectively. Increased numbers of E7-specific IFN-gamma secreting CD8+ T cells were detected in all patients after vaccination. Swelling and induration (i.e., a positive DTH response) to the intradermal injection of HPV E7 oncoprotein and/or irradiated autologous tumor cells were detected in two patients after six vaccinations. No objective clinical responses were observed. However, both patients who developed a positive DTH to the vaccine experienced a slow tumor progression (i.e., 13 months survival) while DTH unresponsive patients died within 5 months from the beginning of therapy.


CONCLUSIONS
Autologous DC pulsed with HPV16/18 E7 proteins can induce systemic B and T cell responses in patients unresponsive to standard treatment modalities. However, treatment-induced immunosuppression may impose severe limitations on the efficacy of active vaccination strategies in late stage cervical cancer patients. DC-based vaccination trials are warranted in immunocompetent cervical cancer patients with early stage disease and/or limited tumor burden, and at significant risk for tumor recurrence or disease progression.
Santin
Alessandro D
AD
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, 4301 W. Markham, Little Rock, AR 72205-7199, USA. santinalessandrod@uams.edu
Bellone
Stefania
S
Palmieri
Michela
M
Ravaggi
Antonella
A
Romani
Chiara
C
Tassi
Renata
R
Roman
Juan J
JJ
Burnett
Alexander
A
Pecorelli
Sergio
S
Cannon
Martin J
MJ
D000328:Adult; D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D004268:DNA-Binding Proteins / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000821:virology; D005260:Female; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008213:Lymphocyte Activation; D009364:Neoplasm Recurrence, Local / Q000276:immunology / Q000628:therapy*; D009856:Oncogene Proteins, Viral / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D013601:T-Lymphocytes / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy*
D000956:Antigens, Viral; D019496:Cancer Vaccines; D004268:DNA-Binding Proteins; C052633:E7 protein, Human papillomavirus type 18; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; C059731:oncogene protein E7, Human papillomavirus type 16