Intratumoral injection of IFN-alpha dendritic cells after dacarbazine activates anti-tumor immunity: results from a phase I trial in advanced melanoma.
BACKGROUND
Advanced melanoma patients have an extremely poor long term prognosis and are in strong need of new therapies. The recently developed targeted therapies have resulted in a marked antitumor effect, but most responses are partial and some degree of toxicity remain the major concerns. Dendritic cells play a key role in the activation of the immune system and have been typically used as ex vivo antigen-loaded cell drugs for cancer immunotherapy. Another approach consists in intratumoral injection of unloaded DCs that can exploit the uptake of a wider array of tumor-specific and individual unique antigens. However, intratumoral immunization requires DCs endowed at the same time with properties typically belonging to both immature and mature DCs (i.e. antigen uptake and T cell priming). DCs generated in presence of interferon-alpha (IFN-DCs), due to their features of partially mature DCs, capable of efficiently up-taking, processing and cross-presenting antigens to T cells, could successfully carry out this task. Combining intratumoral immunization with tumor-destructing therapies can induce antigen release in situ, facilitating the injected DCs in triggering an antitumor immune response.


METHODS
We tested in a phase I clinical study in advanced melanoma a chemo-immunotherapy approach based on unloaded IFN-DCs injected intratumorally one day after administration of dacarbazine. Primary endpoint of the study was treatment safety and tolerability. Secondary endpoints were immune and clinical responses of patients.


RESULTS
Six patients were enrolled, and only three completed the treatment. The chemo-immunotherapy was well tolerated with no major side effects. Three patients showed temporary disease stabilization and two of them showed induction of T cells specific for tyrosinase, NY-ESO-1 and gp100. Of interest, one patient showing a remarkable long-term disease stabilization kept showing presence of tyrosinase specific T cells in PBMC and high infiltration of memory T cells in the tumor lesion at 21 months.


CONCLUSIONS
We tested a chemo-immunotherapeutic approach based on IFN-DCs injected intratumorally one day after DTIC in advanced melanoma. The treatment was well tolerated, and clinical and immunological responses, including development of vitiligo, were observed, therefore warranting additional clinical studies aimed at evaluating efficacy of this approach.


BACKGROUND
Trial Registration Number not publicly available due to EudraCT regulations: https://www.clinicaltrialsregister.eu/doc/EU_CTR_FAQ.pdf.
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. carmela.rozera@iss.it.
Carmela
C
Rozera
IV Dermatology Oncology Unit, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), via Monti Creta 104, Rome, 00167, Italy. G.AntoniniCappellini@idi.it.
Giancarlo Antonini
GA
Cappellini
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. giuseppina.dagostino@iss.it.
Giuseppina
G
D'Agostino
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. laura.santodonato@iss.it.
Laura
L
Santodonato
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. luciano.castiello@iss.it.
Luciano
L
Castiello
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. francesca.urbani@iss.i.
Francesca
F
Urbani
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. iole.macchia@iss.it.
Iole
I
Macchia
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. eleonora.arico@iss.it.
Eleonora
E
Aricò
Immunohematology and Transfusion Medicine Unit, Sapienza University of Rome, Sant'Andrea Hospital, via di Grottarossa 1035, Rome, 00189, Italy. ida.casorelli@ospedalesantandrea.it.
Ida
I
Casorelli
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. paola.sestili@iss.it.
Paola
P
Sestili
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. enrica.montefiore@iss.it.
Enrica
E
Montefiore
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. domenica.monque@iss.it.
Domenica
D
Monque
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. davide.carlei@iss.it.
Davide
D
Carlei
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. mariarosaria.napolitano@iss.it.
Mariarosaria
M
Napolitano
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. paola.rizza@iss.it.
Paola
P
Rizza
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. federica.moschella@iss.it.
Federica
F
Moschella
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. carla.buccione@iss.it.
Carla
C
Buccione
National AIDS Center, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. roberto.belli@iss.it.
Roberto
R
Belli
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. enrico.proietti@iss.it.
Enrico
E
Proietti
Immunohematology and Transfusion Medicine Unit, Sapienza University of Rome, Sant'Andrea Hospital, via di Grottarossa 1035, Rome, 00189, Italy. antonnio.pavan@uniroma1.it.
Antonio
A
Pavan
IV Dermatology Oncology Unit, Istituto Dermopatico dell'Immacolata, Istituto di Ricovero e Cura a Carattere Scientifico (IDI-IRCCS), via Monti Creta 104, Rome, 00167, Italy. paolo.marchetti@ospedalesantandrea.it.|Department of Oncology, Sapienza University of Rome, Sant'Andrea Hospital, via di Grottarossa 1035, Rome, 00189, Italy. paolo.marchetti@ospedalesantandrea.it.
Paolo
P
Marchetti
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. filippo.belardelli@iss.it.
Filippo
F
Belardelli
Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome, 00161, Italy. imerio.capone@iss.it.
Imerio
I
Capone
D000328:Adult; D000368:Aged; D000951:Antigens, Neoplasm / Q000378:metabolism; D019496:Cancer Vaccines / Q000276:immunology; D003131:Combined Modality Therapy / Q000379:methods; D003606:Dacarbazine / Q000737:chemistry*; D003713:Dendritic Cells / Q000166:cytology*; D004358:Drug Therapy / Q000379:methods*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D015552:Injections, Intralesional; D016898:Interferon-alpha / Q000378:metabolism*; D007963:Leukocytes, Mononuclear / Q000166:cytology; D008297:Male; D008545:Melanoma / Q000628:therapy*; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000378:metabolism; D014820:Vitiligo / Q000139:chemically induced; D058951:gp100 Melanoma Antigen / Q000378:metabolism
D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D019496:Cancer Vaccines; D016898:Interferon-alpha; D008565:Membrane Proteins; D058951:gp100 Melanoma Antigen; D003606:Dacarbazine; D014442:Monophenol Monooxygenase