Romero, P.J. (Pedro J.)
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- Quantitative and qualitative impairments in dendritic cell subsets of patients with ovarian or prostate cancer(Elsevier, 2020) Monique-de-Vries, I.J. (Ingrid Jolanda); Mastelic-Gavillet, B. (Beatris); Kandalaft, L.E. (Lana E.); Vigano, S. (Selena); Coukos, G. (George); Jichlinski, P. (Patrice); Lozano, L.E. (Leyder Elena); Derre, L. (Laurent); Harari, A. (Alexandre); Romero, P.J. (Pedro J.); Dartiguenave, F. (Florence); Inoges, S. (Susana); Melero, I. (Ignacio); Wyss, T. (Tania); Sarivalasis, A. (Apostolos)Background Dendritic cells (DCs) are the most efficient antigen-presenting cells, hence initiating a potent and cancer-specific immune response. This ability (mainly using monocyte-derived DCs) has been exploited in vaccination strategies for decades with limited clinical efficacy. Another alternative would be the use of conventional DCs (cDCs) of which at least three subsets circulate in human blood: cDC1s (CD141bright), cDC2s (CD1c+) and plasmacytoid DCs. Despite their paucity, technical advances may allow for their selection and clinical use. However, many assumptions concerning the DC subset biology depend on observations from mouse models, hindering their translational potential. In this study, we characterise human DCs in patients with ovarian cancer (OvC) or prostate cancer (PrC). Patients and methods Whole blood samples from patients with OvC or PrC and healthy donors (HDs) were evaluated by flow cytometry for the phenotypic and functional characterisation of DC subsets. Results In both patient groups, the frequency of total CD141+ DCs was lower than that in HDs, but the cDC1 subset was only reduced in patients with OvC. CD141+ DCs showed a reduced response to the TLR3 agonist poly (I:C) in both groups of patients. An inverse correlation between the frequency of cDC1s and CA125, the OvC tumour burden marker, was observed. Consistently, high expression of CLEC9A in OvC tissue (The Cancer Genome Atlas data set) indicated a better overall survival. Conclusions cDC1s are reduced in patients with OvC, and CD141+ DCs are quantitatively and qualitatively impaired in patients with OvC or PrC. CD141+ DC activation may predict functional impairment. The loss of cDC1s may be a bad prognostic factor for patients with OvC.
- The clinical application of cancer immunotherapy based on naturally circulating dendritic cells(BMJ, 2019) Dzionek, A. (Andrzej); Kandalaft, L.E. (Lana E.); Sancho, D. (David); Coukos, G. (George); Wculek, S.K. (Stefanie K.); Romero, P.J. (Pedro J.); Schwarze, J.K. (Julia Katharina); Schreibelt, G. (Gerty); Vries, J. (Jolanda) de; Neyns, B. (Bart); Melero, I. (Ignacio); Rabold, K. (Katrin); Bol, K.F. (Kalijn F.); Teijeira, A. (Álvaro)Dendritic cells (DCs) can initiate and direct adaptive immune responses. This ability is exploitable in DC vaccination strategies, in which DCs are educated ex vivo to present tumor antigens and are administered into the patient with the aim to induce a tumor-specific immune response. DC vaccination remains a promising approach with the potential to further improve cancer immunotherapy with little or no evidence of treatment-limiting toxicity. However, evidence for objective clinical antitumor activity of DC vaccination is currently limited, hampering the clinical implementation. One possible explanation for this is that the most commonly used monocyte-derived DCs may not be the best source for DC-based immunotherapy. The novel approach to use naturally circulating DCs may be an attractive alternative. In contrast to monocyte-derived DCs, naturally circulating DCs are relatively scarce but do not require extensive culture periods. Thereby, their functional capabilities are preserved, the reproducibility of clinical applications is increased, and the cells are not dysfunctional before injection. In human blood, at least three DC subsets can be distinguished, plasmacytoid DCs, CD141+ and CD1c+ myeloid/conventional DCs, each with distinct functional characteristics. In completed clinical trials, either CD1c+ myeloid DCs or plasmacytoid DCs were administered and showed encouraging immunological and clinical outcomes. Currently, also the combination of CD1c+ myeloid and plasmacytoid DCs as well as the intratumoral use of CD1c+ myeloid DCs is under investigation in the clinic. Isolation and culture strategies for CD141+ myeloid DCs are being developed. Here, we summarize and discuss recent clinical developments and future prospects of natural DC-based immunotherapy.
- Defining the Critical Hurdles in Cancer Immunotherapy(Biomed Central, 2011) Kotlan, B. (Beatrix); Ottensmeier, C. (Christian); Zwierzina, H. (Heinz); Butterfield, L.H. (Lisa H.); Nelief, C. (Cornelious); Gajewski, T.F. (Thomas F.); Borden, E. (Ernest); Bonorino, C. C. (Cristina C.); Song, W. (Wenru); Hoos, A. (Axel); Grizzi, F. (Fabio); Characiejus, D. (Dainius); Galon, J. (Jerome); Kaufman, H.L. (Howard L.); Coukos, G. (George); Kawakami, K. (Koji); Dillman, R.O. (Robert O.); Ribas, A. (Antoni); Herberman, R.B. (Ronald B.); Kalinski, P. (Pawel); Durrant, L.G. (Lindy G.); Hwu, P. (Patrick); Aamdal, S. (Steinar); Straten, P.T. (Per Thor); Wang, E. (Ena); Finke, J.H. (James H.); Romero, P.J. (Pedro J.); Withington, T. (Tara); Schendel, D. J. (Dolores J.); Scheper, R.J. (Rik J.); Disis, M.L. (Mary L.); Old, LL.J. (LLoyd J.); Allison, J.P. (James P.); Singh-Jasuja, H. (Harpreet); Kroemer, G. (Guido); Guida, M. (Michele); Dranoff, G. (Glenn); Kawakami, Y. (Yutaka); Hodi, F.S. (F. Stephen); Jaffee, E.M. (Elizabeth M.); Maio, M. (Michele); Maccalli, C. (Cristina); Salem, M.L. (Mohamed L.); Van-Der-Burg, S.H. (Sjoerd H.); Gollob, J.A. (Jared A.); Khleif, S.N. (Samir N.); Bergmann, L. (Lothar); Wigginton, J.M. (Jon M.); Xiao, W. (Weihua); Qin, S. (Shukui); Bartunkova, J. (Jirina); Britten, C.M. (Cedrik M.); Nelson, B. (Brad); Berinstein, N. (Neil); Rivoltini, L. (Licia); Proietti, E. (Enrico); Melero, I. (Ignacio); Mastrangelo, M.J. (Michael J.); Kiessling, R. (Rolf); Chang, A.E. (Alfred E.); Keilholtz, U. (Ulrich); Parmiani, G. (Giorgio); Janetzki, S. (Sylvia); Zitvogel, L. (Laurence); Seliger, B. (Barbara); Rees, R. (Robert); O'Donnell-Tormey, J. (Jill); Levitsky, H.I. (Hyam I.); Hakansson, L. (Leif); Nishimura, M.I. (Michael I.); Marschner, J-P. (Jens-Peter); Wolchok, J.D. (Jedd D.); Ohashi, P.S. (Pamela S.); Sharma, P. (Padmanee); Imai, K. (Kohzoh); Winter, H. (Hauke); Ritter, G. (Gerd); Odunsi, K. (Kunle); Fox, B.A. (Bernard A.); Von Hoegen, P. (Paul); Gruijl, T. (Tanja); Nicolini, A. (Andrea); Welters, M. J. (Maris J.); Hege, K. (Kristen); Lotze, M.T. (Michael T.); Murphy, W.J. (William J.); Atkins, M.B. (Michael B.); Dolstra, H. (Harry); Lapointe, R. (Rejean); Masucci, G. (Giuseppe); Cao, X. (Xuetao); Tian, Z. (Zigang); Ascierto, P.A. (Paolo Antonio); Huber, C. (Christoph); Tahara, H. (Hideaki); Pawelec, G. (Graham); June, C.H. (Carl H.); Carson, W.E. (William E.); Papamichail, M. (Michael); Choudhury, A.R. (A. Raja); Marincola, F.M. (Francesco M.); Shiku, H. (Hiroshi); Bramson, J.L. (Jonathan L.); Ridolfi, R. (Ruggero); Gouttefangeas, C. (Cecile)ABSTRACT: Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better. Innovative strategies need to move into early stage clinical trials as quickly as it is safe, and if successful, these therapies should efficiently obtain regulatory approval and widespread clinical application. In late 2009 and 2010 the Society for Immunotherapy of Cancer (SITC), convened an "Immunotherapy Summit" with representatives from immunotherapy organizations representing Europe, Japan, China and North America to discuss collaborations to improve development and delivery of cancer immunotherapy. One of the concepts raised by SITC and defined as critical by all parties was the need to identify hurdles that impede effective translation of cancer immunotherapy. With consensus on these hurdles, international working groups could be developed to make recommendations vetted by the participating organizations. These recommendations could then be considered by regulatory bodies, governmental and private funding agencies, pharmaceutical companies and academic institutions to facilitate changes necessary to accelerate clinical translation of novel immune-based cancer therapies. The critical hurdles identified by representatives of the collaborating organizations, now organized as the World Immunotherapy Council, are presented and discussed in this report. Some of the identified hurdles impede all investigators, others hinder investigators only in certain regions or institutions or are more relevant to specific types of immunotherapy or first-in-humans studies. Each of these hurdles can significantly delay clinical translation of promising advances in immunotherapy yet be overcome to improve outcomes of patients with cancer.
- Bivalent therapeutic vaccine against HPV16/18 genotypes consisting of a fusion protein between the extra domain A from human fibronectin and HPV16/18 E7 viral antigens(2020) Domingos-Pereira, S. (Sonia); Echeverria, I. (Itziar); Lozano-Moreda, T. (Teresa); Carrascosa, J.L. (José L.); Romero, P.J. (Pedro J.); Gomez, T. (Timothy); Hervas-Stubbs, S. (Sandra); Zürcher, T. (Thomas); Casares, N. (Noelia); Rodriguez, M.J. (María Josefa); Nardelli-Haefliger, D. (Denise); Sarobe, P. (Pablo); Villanueva, L. (Lorea); Belsue, V. (Virginia); Arribillaga, L. (Laura); Lasarte, J.J. (Juan José)Background In vivo targeting of human papillomavirus (HPV) derived antigens to dendritic cells might constitute an efficient immunotherapeutic strategy against cervical cancer. In previous works, we have shown that the extra domain A from murine fibronectin (mEDA) can be used to target antigens to toll-like receptor 4 (TLR4) expressing dendritic cells and induce strong antigen-specific immune responses. In the present study, we have produced a bivalent therapeutic vaccine candidate consisting of the human EDA (hEDA) fused to E7 proteins from HPV16 and HPV18 (hEDA-HPVE7-16/18) and evaluate its potential as a therapeutic vaccine against cervical cancer. Materials and methods Recombinant fusion proteins containing HPV E7 proteins from HPV16 and HPV18 virus subtypes fused to hEDA were produced and tested in vitro on their capacity to bind TLR4 and induce the production of tumor necrosis factor-α or interleukin (IL)-12 by human monocytes and dendritic cells. The immunogenicity and potential therapeutic activity of the vaccine in combination with cisplatin or with the TLR3 agonist molecules polyinosinic‐polycytidylic acid (Poly IC) or Poly ICLC was evaluated in mice bearing subcutaneous or genital orthotopic HPV16 TC-1 tumors. Results hEDA-HPVE7-16/18 prototype vaccine binds human TLR4 and stimulate TLR4-dependent signaling pathways and IL-12 production by human monocytederived dendritic cell. Vaccination with hEDA-HPVE7-16/18 induced strong HPVE7-specific Cytotoxic T lymphocyte (CTL) responses and eliminated established tumors in the TC-1-based tumor model. The antitumor efficacy was significantly improved by combining the fusion protein with cisplatin or with the TLR-3 ligand Poly IC and especially with the stabilized analog Poly ICLC. Moreover, hEDAHPVE7-16/18+Poly ICLC induced full tumor regression in 100% of mice bearing orthotopic genital HPV tumors. Conclusion Our results suggest that this therapeutic vaccine formulation may be an effective treatment for cervical tumors that do not respond to current therapies.