Adjuvant Autologous Melanoma Vaccine for Macroscopic Stage III Disease: Survival, Biomarkers, and Improved Response to CTLA-4 Blockade

Abstract

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.

Phenotype-based variation as a biomarker of sensitivity to molecularly targeted therapy in melanoma

“…Cells were initially tested for melanoma markers S100, MART-1 and gp100 to differentiate them from non-melanoma cells 20 . As a further measure of specificity, gene expression data obtained from all cell lines via C-MAP technology was used to generate two gene lists representing “melanoma” (MEL) and “fibroblasts” (FIB) like qualities using a previously defined algorithm 18 .…”

“…Primary melanoma cell lines used in this study were previously described 19, 20 . All cell lines (primary and commercial) were incubated in humidified incubators supplied with 5% CO 2 and cultured in RPMI1640 medium supplemented with 10% FBS, 1% 10K/10K Penicillin-Streptomycin (P/S Solution, Lonza, Basel, Switzerland) and 1% 200mM L-Glutamine (L-Glu, Lonza, Basel, Switzerland).…”

“…” These 223 probesets constitute the “gene list #1”. Standardized expression values of these probesets obtained from the C-MAP microarray data of primary melanoma cell lines 20 were used for hierarchical clustering analysis using Euclidean distance as the similarity metric and complete linkage as the clustering method in Cluster3.0 software. Results were visualized in JavaTreeView.…”

Tumor-derived granulocyte colony-stimulating factor diminishes efficacy of breast tumor cell vaccines

“…Common mechanisms that cancer cells use during immune escape include (1) downregulation of major histocompatibility complex (MHC I/II) molecules and development of defects in antigen presentation; (2) downregulation of costimulatory molecules, such as B7–1 and B7–2; (3) upregulation of immunoinhibitory molecules, such as programmed death-ligand 1 (PD-L1); (4) loss or modification of tumor-associated antigen(s); and (5) increased production of immunosuppressive factors such as indoleamine 2,3-dioxygenase (IDO), IL-10 and tumor growth factor (TGF)β [ 21 ]. As a result, nearly all ATCVs currently under development utilize strategies to boost tumor cell immunogenicity through one or more of the following: transfection of autologous tumor cells with costimulatory molecules [ 22 – 26 ], conjugation of immunostimulatory moieties to autologous tumor cells [ 10 , 27 ]; co-formulation with immunostimulatory molecules [ 6 , 8 , 27 – 30 ]; or engineering autologous tumor cells to secrete adjuvant cytokines [ 9 , 31 – 41 ]. Employing these strategies has demonstrated significant increases in antitumor immunity against various malignancies in clinical studies [ 8 – 10 , 26 , 27 , 33 , 36 , 37 , 39 , 41 – 43 ].…”

RECIST 1.1 AND irRC FOR RESPONSE ASSESMENT IN PATIENTS WITH DISSEMINATED CUTANEOUS MELANOMA TREATED WITH IPILIMUMAB OR DENDRITIC CELL VACCINE

“…Причиной этого явления может быть влияние вакцинотерапии на эффективность последующего лечения. Lotem et al показали, что пациенты, получившие раннюю вакцинотерапию и последующую терапию ипилимумабом, имеют более длительную выживаемость относительно пациентов, получавших монотерапию IPI: 5-летняя выживаемость -КЛИНИЧЕСКИЕ ИССЛЕДОВАНИЯ 46 и 19 % соответственно (относительный риск смерти -0,46, р=0,07) [16]. В исследовании, опубликованном нами ранее, в котором сравнивались эффективность смешанной терапии DCV+IPI и монотерапии IPI, 3-летняя выживаемость составила 59 и 15 % (относительный риск смерти -0,52, р=0,049) [17].…”