Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade.
Background. There is not yet an agreed adjuvant treatment for melanoma patients with American Joint Committee on Cancer stages III B and C. We report administration of an autologous melanoma vaccine to prevent disease recurrence. Patients and Methods. 126 patients received eight doses of irradiated autologous melanoma cells conjugated to dinitrophenyl and mixed with BCG. Delayed type hypersensitivity (DTH) response to unmodified melanoma cells was determined on the vaccine days 5 and 8. Gene expression analysis was performed on 35 tumors from patients with good or poor survival. Results. Median overall survival was 88 months with a 5-year survival of 54%. Patients attaining a strong DTH response had a significantly better (p = 0.0001) 5-year overall survival of 75% compared with 44% in patients without a strong response. Gene expression array linked a 50-gene signature to prognosis, including a cluster of four cancer testis antigens: CTAG2 (NY-ESO-2), MAGEA1, SSX1, and SSX4. Thirty-five patients, who received an autologous vaccine, followed by ipilimumab for progressive disease, had a significantly improved 3-year survival of 46% compared with 19% in nonvaccinated patients treated with ipilimumab alone (p = 0.007). Conclusion. Improved survival in patients attaining a strong DTH and increased response rate with subsequent ipilimumab suggests that the autologous vaccine confers protective immunity.
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Michal
M
Lotem
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Sharon
S
Merims
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Stephen
S
Frank
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Tamar
T
Hamburger
Departments of Surgery, Hadassah Hebrew University Hospital, Mount Scopus Campus, 91240 Jerusalem, Israel.
Aviram
A
Nissan
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Luna
L
Kadouri
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Jonathan
J
Cohen
Department of Molecular Cell Biology, Weizmann Institute of Science, 7610001 Rehovot, Israel.
Ravid
R
Straussman
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Galit
G
Eisenberg
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Shoshana
S
Frankenburg
Departments of Surgery, Hadassah Hebrew University Hospital, Mount Scopus Campus, 91240 Jerusalem, Israel.
Einat
E
Carmon
Departments of Surgery, Hadassah Hebrew University Hospital, Mount Scopus Campus, 91240 Jerusalem, Israel.
Bilal
B
Alaiyan
Department of Surgery, Tel Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel.
Shlomo
S
Shneibaum
Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
Zeynep
Z
Ozge Ayyildiz
Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
Murat
M
Isbilen
Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
Kerem
K
Mert Senses
Department of Oncology, Tel Aviv Sourasky Medical Center, 64239 Tel Aviv, Israel.
Ilan
I
Ron
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Hanna
H
Steinberg
Genomic Data Analysis Unit, Hebrew University Medical School, 91120 Jerusalem, Israel.
Yoav
Y
Smith
Department of Surgery, Bnai Zion Medical Center, 31048 Haifa, Israel.
Eitan
E
Shiloni
Department of Molecular Biology and Genetics, Bilkent University, 06800 Ankara, Turkey.
Ali Osmay
AO
Gure
Sharett Institute of Oncology, Hadassah Hebrew University Hospital, Ein Karem Campus, 91120 Jerusalem, Israel.
Tamar
T
Peretz
D000276:Adjuvants, Immunologic; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents; D015415:Biomarkers; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000009:adverse effects / Q000276:immunology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003131:Combined Modality Therapy; D020869:Gene Expression Profiling; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D053208:Kaplan-Meier Estimate; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009367:Neoplasm Staging; D016896:Treatment Outcome; D014611:Vaccination; D055815:Young Adult
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D015415:Biomarkers; D060908:CTLA-4 Antigen; D019496:Cancer Vaccines; D000074324:Ipilimumab