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1. Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients

Author

Mélanie Saint-Jean, Anne-Chantal Knol, Christelle Volteau, Gaëlle Quéreux, Lucie Peuvrel, Anabelle Brocard, Marie-Christine Pandolfino, Soraya Saiagh, Jean-Michel Nguyen, Christophe Bedane, Nicole Basset-Seguin, Amir Khammari, and Brigitte Dréno

Subjects
Immunologic diseases. Allergy, RC581-607
Abstract

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

Published
2018
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2. Tissue biomarkers in melanoma patients treated with TIL.

Author

Anne-Chantal Knol, Jean-Michel Nguyen, Marie-Christine Pandolfino, Gaëlle Quéreux, Anabelle Brocard, Lucie Peuvrel, Mélanie Saint-Jean, Soraya Saiagh, Amir Khammari, and Brigitte Dréno

Subjects
Medicine, Science
Abstract

While treating stage III melanoma patients with autologous therapeutic TIL in an adjuvant setting, we previously reported a significant benefit of treatment on both progression-free survival and overall survival in patients with only one invaded lymph node (early stage III) compared to patients with more than one invaded lymph nodes (advanced stage III). In this context, in order to understand the difference of activity of TIL therapy according to the progression of the illness at stage III, the first objective of the present study was to determine potential differences in the characteristics of TIL populations obtained from an early stage III and a more advanced stage III when tumor burden is more important. The second objective was to determine possible differences in tissue expression level of several molecules involved in interactions between tumor cells and T cells between early and advanced stage III considering that the tumor microenvironment of invaded lymph nodes could become more tolerant with the progression of the disease. A total of 47 samples of melanoma invaded LN from stage IIIb (AJCC 2007) melanoma patients treated with TIL plus IL-2 were included in this study. We confirmed that both PFS and OS were significantly associated to the presence of tumor-reactive T-cells among TIL injected to the patients and that these tumor reactive T cells were more frequently observed at the early stage III. Moreover, while analyzing the expression of 17 markers on 34/47 tumor specimens using immunohistochemistry, we identified that 3 tissue markers involved in interactions between melanoma cells and T cells have a significant difference of expression between early and advanced stage III: MHC class I, adhesion molecule ICAM-1 and the co-stimulation molecule LFA-3 had a significantly weaker expression in melanoma tissue specimens from advanced stage III. In addition, the expression of the alpha chain of the IL-2 receptor (CD25) and the nuclear transcription factor Foxp3 was significantly increased in the melanoma tissue specimens from advanced stage III. Our results suggest differences in the immunological status of the tumor microenvironment between early and advanced stage III, which could explain the difference in clinical response to TIL infusion in an adjuvant setting between early and advanced stage III.

Published
2012
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3. Severe dermatophytosis in solid organ transplant recipients: A French retrospective series and literature review

Author

Dany Anglicheau, Claire Rouzaud, Roderick J. Hay, Jean-David Bouaziz, Olivier Chosidow, Marie-Elisabeth Bougnoux, Anne Scemla, Anabelle Brocard, Fanny Lanternier, Olivier Lortholary, Sylvie Fraitag, Nicolas Dupin, Service des Maladies infectieuses et tropicales [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Dermatologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor, Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'anatomie pathologique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Réseau CENTAURE, Département de Néphrologie [CHU Necker], Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Hôpital Cochin [AP-HP], Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Parasitologie-Mycologie, Service de Microbiologie [Hôpital Necker-Enfants-Malades, Paris], Assistance Publique - Hôpitaux de Paris, King's College Hospital (KCH), Centre National de Référence Mycoses Invasives et Antifongiques - National Reference Center Invasive Mycoses & Antifungals (CNRMA), Institut Pasteur [Paris], Société de Pathologie Infectieuse de Langue Française (SPILF)Société Française de Mycologie Médicale (SFMM)Groupe Peau et Greffe d'Organe (GPGO) of the Société Française de Dermatologie (SFD), Institut Pasteur [Paris] (IP), Université Paris Descartes - Paris 5 (UPD5)-CHU Necker - Enfants Malades [AP-HP]-Institut des Maladies Génétiques Imagine [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Henri-Mondor, CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris (AP-HP), and CHU Cochin [AP-HP]

Subjects
Adult, Male, 0301 basic medicine, medicine.medical_specialty, Posaconazole, dermatophytosis, Majocchi's granuloma, medicine.medical_treatment, 030106 microbiology, deep dermatophytosis, Trichophyton rubrum, Severity of Illness Index, [SDV.MP.PRO]Life Sciences [q-bio]/Microbiology and Parasitology/Protistology, Organ transplantation, Immunocompromised Host, 03 medical and health sciences, Tinea, Trichophyton, Severity of illness, Humans, Medicine, 10. No inequality, Solid-organ transplant, Kidney transplantation, ComputingMilieux_MISCELLANEOUS, Aged, Retrospective Studies, Transplantation, immunosuppression, business.industry, Deep dermatophytosis, Immunosuppression, Organ Transplantation, Middle Aged, medicine.disease, Kidney Transplantation, Dermatology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Transplant Recipients, 3. Good health, Infectious Diseases, Terbinafine, Female, France, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug
Abstract

OBJECTIVE Severe dermatophytosis is described in immunocompromised patients with defective cellular immunity. We report here a large series and a literature review of severe dermatophytosis in solid-organ transplant (SOT) recipients. METHOD The data main source was a national French retrospective study of severe dermatophytosis in SOT recipients between 2010 and 2016. Inclusion criteria were the presence of dermatophytes in skin culture and 1 severity criteria: dermal invasion by dermatophytes (invasive dermatophytosis) or involvement of at least two body sites or >10% of body surface area (extensive dermatophytosis). RESULTS A total of 12 patients were included (8 men, median age of 56 years [range: 33-71]). Of the 12 patients, 10 underwent kidney transplantation. The median time from transplantation to severe dermatophytosis diagnosis was 16 months [range: 2-94]. Clinical signs of superficial dermatophytosis were present in 8/12 patients before the emergence of severe dermatophytosis. Nine patients had invasive forms and three extensive ones, and nodules of the lower extremities were found in eight. Trichophyton rubrum was isolated in 11 cases. First-line treatment was terbinafine (7/12), posaconazole (3/12), or topical treatment alone (2/12). Immunosuppressive therapy was reduced in 3 patients because of associated infections. Complete response was obtained for 3/3 and 5/9 patients with extensive or invasive forms, respectively, after a median treatment's duration of 2.5 [range: 1.5-5] months and 7.5 months [range: 4-12]. Unrelated deaths (n = 2) and graft function impairment (n = 3) occurred. CONCLUSION Severe dermatophytosis is a late complication in SOT recipients presenting with lower limb nodules, which might be prevented by prompt treatment of superficial dermatophytosis.

Published
2018
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4. Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes in Advanced Melanoma Patients

Author

Christophe Bedane, Anabelle Brocard, Mélanie Saint-Jean, Lucie Peuvrel, Soraya Saiagh, Gaëlle Quéreux, Amir Khammari, Nicole Basset-Seguin, Anne-Chantal Knol, Marie-Christine Pandolfino, Brigitte Dréno, Christelle Volteau, Jean-Michel Nguyen, Clinical and Translational Research in Skin Cancer (CRCINA-ÉQUIPE 2), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Département de Dermato-Cancerologie [CHU Nantes], Centre hospitalier universitaire de Nantes (CHU Nantes), Direction de la Recherche [CHU Nantes], Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), Service d'Evaluation Médicale et d'Epidémiologie [CHU Nantes] (SEME), Service de Dermatologie [CHU Limoges], CHU Limoges, Service de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Clinical and translational research in skin cancer ( CRCINA - Département INCIT - Equipe 2 ), Centre de recherche de Cancérologie et d'Immunologie / Nantes - Angers ( CRCINA ), Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Université d'Angers ( UA ) -Université de Nantes ( UN ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche en Santé de l'Université de Nantes ( IRS-UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Unité de Thérapie Cellulaire et Génique [CHU Nantes] ( UTCG ), Hôtel-Dieu-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre d’Investigation Clinique de Nantes ( CIC Nantes ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'Evaluation Médicale et d'Epidémiologie [CHU Nantes] ( SEME ), Département de Dermatologie [AP-HP Hôpital Saint-Louis], Hopital Saint-Louis, Assistance Publique – Hôpitaux de Paris ( AP-HP ), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Oncology, Male, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Article Subject, medicine.medical_treatment, Immunology, chemical and pharmacologic phenomena, [SDV.CAN]Life Sciences [q-bio]/Cancer, Immunotherapy, Adoptive, T-Lymphocytes, Regulatory, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, Cell therapy, 03 medical and health sciences, 0302 clinical medicine, Lymphocytes, Tumor-Infiltrating, [SDV.CAN] Life Sciences [q-bio]/Cancer, Internal medicine, medicine, Immunology and Allergy, Humans, Stage IIIC, Adverse effect, Melanoma, Cells, Cultured, Neoplasm Staging, Retrospective Studies, business.industry, Tumor-infiltrating lymphocytes, Therapeutic effect, Remission Induction, Antibodies, Monoclonal, Forkhead Transcription Factors, hemic and immune systems, General Medicine, Immunotherapy, medicine.disease, Survival Analysis, 3. Good health, Regimen, 030220 oncology & carcinogenesis, Interleukin-2, Female, business, lcsh:RC581-607, 030215 immunology, Follow-Up Studies, Research Article
Abstract

Immunotherapy for melanoma includes adoptive cell therapy with autologous tumor-infiltrating lymphocytes (TILs). This monocenter retrospective study was undertaken to evaluate the efficacy and safety of this treatment of patients with advanced melanoma. All advanced melanoma patients treated with TILs using the same TIL expansion methodology and same treatment interleukin-2 (IL-2) regimen between 2009 and 2012 were included. After sterile intralesional excision of a cutaneous or subcutaneous metastasis, TILs were produced according to a previously described method and then infused into the patient who also received a complementary subcutaneous IL-2 regimen. Nine women and 1 man were treated for unresectable stage IIIC (n=4) or IV (n=6) melanoma. All but 1 patient with unresectable stage III melanoma (1st line) had received at least 2 previous treatments, including anti-CTLA-4 antibody for 4. The number of TILs infused ranged from 0.23 × 109 to 22.9 × 109. Regarding safety, no serious adverse effect was reported. Therapeutic responses included a complete remission, a partial remission, 2 stabilizations, and 6 progressions. Among these 4 patients with clinical benefit, 1 is still alive with 9 years of follow-up and 1 died from another cause after 8 years of follow-up. Notably, patients treated with high percentages of CD4 + CD25 + CD127lowFoxp3+ T cells among their TILs had significantly shorter OS. The therapeutic effect of combining TILs with new immunotherapies needs further investigation.

Published
2018
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5. Clinical significance of BRAF mutation status in circulating tumor DNA of metastatic melanoma patients at baseline

Author

Anne Chantal Knol, Amir Khammari, Guillaume Herbreteau, Anabelle Brocard, Audrey Vallée, Brigitte Dréno, Sandrine Théoleyre, Gaëlle Quéreux, Emilie Varey, Aurélie Gaultier, Jean-Michel Nguyen, Lucie Peuvrel, Mélanie Saint-Jean, Marc G. Denis, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), SEB-PIMESP, Centre hospitalier universitaire de Nantes (CHU Nantes), CIC biothérapies CBT 0503 [Nantes], Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), and Bernardo, Elizabeth

Subjects
Adult, Male, Proto-Oncogene Proteins B-raf, 0301 basic medicine, Pathology, medicine.medical_specialty, plasma DNA, overall survival, Mutant, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, Biology, medicine.disease_cause, Biochemistry, S100 protein, Circulating Tumor DNA, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, medicine, Humans, Clinical significance, Neoplasm Metastasis, Melanoma, Molecular Biology, Aged, Mutation, L-Lactate Dehydrogenase, S100 Proteins, Cancer, Middle Aged, medicine.disease, 3. Good health, 030104 developmental biology, BRAF mutation, chemistry, Circulating tumor DNA, 030220 oncology & carcinogenesis, Cancer research, Female, France, DNA, metastatic melanoma
Abstract

International audience; Circulating tumor DNA is a promising non-invasive tool for cancer monitoring. The main objective of our work was to investigate the relationship between mutant BRAF DNA in plasma and clinical response. Thirty-eight stage IV patients with a V600 mutated BRAF melanoma were included prior to any treatment. DNA was extracted from plasma and mutant DNA was detected using the amplification-refractory mutation system method. Before the beginning of any treatment, the corresponding BRAF mutation was detected in 29 of the 38 tested plasma samples (76.3% positive per cent agreement). We observed a strong correlation between the presence of circulating mutated DNA and overall survival (OS; P=.02), and with the number of metastatic sites (P=.01). The presence of circulating mutated DNA was also strongly correlated with serum LDH activity (P

Published
2016
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6. Dysgeusia and weight loss under treatment with vismodegib: benefit of nutritional management

Author

Adam Jirka, Marie Le Moigne, Lucie Peuvrel, Brigitte Dréno, Amir Khammari, Anabelle Brocard, Mélanie Saint-Jean, Aurélie Gaultier, Gaëlle Quéreux, Dominique Darmaun, Hôpital Hôtel-Dieu [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM), Immunobiologie fondamentale et clinique, Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie des Adaptations Nutritionnelles (PhAN), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and SEB

Subjects
Male, medicine.medical_specialty, Weight loss, Skin Neoplasms, Pyridines, Vismodegib, Antineoplastic Agents, Pilot Projects, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dysgeusia, Nutritional management, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Medicine, Humans, Cumulative incidence, Anilides, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Aged, 2. Zero hunger, Aged, 80 and over, business.industry, Incidence (epidemiology), Malnutrition, Middle Aged, 3. Good health, Surgery, Oncology, Carcinoma, Basal Cell, 030220 oncology & carcinogenesis, Cohort, Female, medicine.symptom, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, medicine.drug, Cohort study
Abstract

International audience; Purpose Whereas vismodegib is effective in the treatment of locally advanced/metastatic basal cell carcinoma, dysgeusia and weight loss are common side effects of such treatment. The main objective of this study was to monitor the nutritional status of vismodegib-treated patients. Secondary objective was to assess the incidence of dysgeusia and the benefit of early nutritional management. Methods This prospective study included all patients who started vismodegib between October 2011 and May 2013 at Nantes University Hospital. Prior to July 2012, patients treated with vismodegib had not received any specific nutritional management (Historical cohort). Body weight and presence of dysgeusia were recorded monthly. Patients treated after July 2012 (Nutrition cohort) were evaluated by a physician of the Nutrition Support Unit and received dietary counseling at vismodegib initiation. A standardized nutritional management protocol was initiated in case of significant weight loss. Results Forty-five patients (21 and 24 in the Nutrition and Historical cohort, respectively) were enrolled. In the Nutrition cohort, five patients (24 %) were undernourished at vismodegib initiation, and the 6-month cumulative incidence of dysgeusia was 71 %. Eight patients (38 %) and 13 patients (54 %) had a weight loss greater than 5 % in the Nutrition and Historical cohort, respectively (p = 0.3727). Conclusion The results of this pilot study suggest the benefit of early nutritional screening. The potential benefit of nutritional support in this setting warrants further investigation.

Published
2016
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7. Treatment of Metastatic Melanoma with Autologous Melan-A/Mart-1-Specific Cytotoxic T Lymphocyte Clones

Author

Jean-Michel Nguyen, Anabelle Brocard, Amir Khammari, Brigitte Dréno, Francine Jotereau, Anne Chantal Knol, Gaëlle Quéreux, Marie-Christine Pandolfino, Nathalie Labarrière, Virginie Vignard, Soraya Saiagh, LABARRIERE, Nathalie, Centre de Recherche en Cancérologie Nantes-Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Centre hospitalier universitaire de Nantes (CHU Nantes), PIMESP [CHU Nantes, Hôpital Saint-Jacques], Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), and Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes)

Subjects
Interleukin 2, Male, Adoptive cell transfer, Skin Neoplasms, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Dacarbazine, Clone (cell biology), Alpha interferon, Skin Pigmentation, [SDV.CAN]Life Sciences [q-bio]/Cancer, Dermatology, CD8-Positive T-Lymphocytes, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, MART-1 Antigen, [SDV.CAN] Life Sciences [q-bio]/Cancer, Antigens, Neoplasm, medicine, Cytotoxic T cell, Humans, Molecular Biology, Melanoma, Aged, business.industry, Cell Biology, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, Adoptive Transfer, 3. Good health, Clone Cells, Neoplasm Proteins, Treatment Outcome, 030220 oncology & carcinogenesis, Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, 030215 immunology, medicine.drug, T-Lymphocytes, Cytotoxic
Abstract

International audience; Immunotherapy by adoptive T-cell transfer aims at maximizing tumor antigen-specific T-cell responses. We treated 14 patients at the metastatic stage in a phase II study with Melan-A-specific T-cell clones generated from patient blood. During the period required for T-cell clone generation, the patients were treated by dacarbazine. Every patient received a T-cell clone suspension followed by subcutaneous injections of interleukin 2 and interferon alpha. Patients were monitored until disease progression occurred. We succeeded in obtaining autologous Melan-A-specific cytotoxic T lymphocyte clones, which were highly reactive against tumor cells for all the patients. Of the 14 patients treated, six (43%) experienced an objective response (CR þ PR) with long-term complete remission for two patients (1 CR for 5 years and 1 CR for 28 months). Furthermore, we showed that all the clinical responses were significantly associated with in vivo expansion of the Melan-A-specific T-cell repertoire. This phenomenon appeared to be significantly associated with clinical responses. Thus, over the course of an adoptive cell transfer, monitoring this melanoma-specific T-cell expansion in patient blood appears crucial for predicting the clinical efficiency of such an immunological approach.

Published
2009
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8. Long-term follow-up of patients treated by adoptive transfer of melanoma tumor-inWltrating lymphocytes as adjuvant therapy for stage III melanoma

Author

Amir Khammari, Sylvain Bercegeay, Marie Christine Pandolfino, Jean-Michel Nguyen, Philippe Lemarre, Christelle Volteau, Francine Jotereau, Brigitte Dréno, Alain Cassidanius, Gaëlle Quéreux, Nathalie Labarrière, Anabelle Brocard, Service de dermatologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes), PIMESP [CHU Nantes, Hôpital Saint-Jacques], Unité de Thérapie Cellulaire et Génique [CHU Nantes] (UTCG), Hôtel-Dieu-Centre hospitalier universitaire de Nantes (CHU Nantes), Recherches en cancérologie, Université de Nantes (UN)-IFR26-Institut National de la Santé et de la Recherche Médicale (INSERM), and LABARRIERE, Nathalie

Subjects
Adult, Oncology, Cancer Research, medicine.medical_specialty, Adoptive cell transfer, Adolescent, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Immunology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Disease-Free Survival, 03 medical and health sciences, Lymphocytes, Tumor-Infiltrating, 0302 clinical medicine, Adjuvants, Immunologic, [SDV.CAN] Life Sciences [q-bio]/Cancer, Recurrence, Internal medicine, medicine, Adjuvant therapy, Humans, Immunology and Allergy, Survivors, Stage (cooking), Melanoma, Lymph node, Aged, Neoplasm Staging, Tumor-infiltrating lymphocytes, business.industry, Immunotherapy, [SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy, Middle Aged, medicine.disease, Adoptive Transfer, 3. Good health, Surgery, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.IMM]Life Sciences [q-bio]/Immunology, Lymph, [SDV.IMM.IMM] Life Sciences [q-bio]/Immunology/Immunotherapy, business, Follow-Up Studies, 030215 immunology
Abstract

The first analysis of our clinical trial on interest of using tumor-infiltrating lymphocytes (TIL) as adjuvant therapy for stage III (regional lymph nodes) melanoma was published in 2002 [5]. The aim of this paper is to update clinical results of 7 years of follow-up after the last treated patient. In the trial conducted between December 1993 and January 1999, patients without any detectable metastases after lymph node excision were randomly assigned to receive either TIL plus interleukin-2 (IL-2) for 2 months, or IL-2 only. The duration of the relapse-free interval was the primary objective. Eighty-eight patients were enrolled in the study. Currently, the last analysis performed in June 2006, after a median follow-up of 114.8 months, did not show change of non-significant extension of the relapse-free interval or overall survival. However, this second analysis strengthens our first hypothesis about the relationship between number of invaded lymph nodes and TIL treatment effectiveness. In the group with only one invaded lymph node, the estimated relapse rate was significantly lower (P adjusted = 0.0219) and the overall survival was increased (P adjusted = 0.0125) in the TIL+IL-2 arm compared with the IL-2 only arm. No differences between the two arms, either with regard to the duration of disease-free survival (P adjusted = 0.38) or overall survival (P adjusted = 0.43), were noted in the group with more than one invaded lymph node, whatever the number of invaded lymph nodes. Treatment was compatible with normal daily activity. This study, with a very long follow up (median of almost 10 years), postulates for the first time relationship between TIL efficiency in stage III melanoma (AJCC) and number of invaded lymph nodes, indicating that tumor burden might be a crucial factor in the production of an effective in vitro expansion of T cells specific for autologous tumor antigen, a finding which could be of value in future vaccine development for the treatment of melanoma.

Published
2007
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9. Is a Single BRAF Wild-Type Test Sufficient to Exclude Melanoma Patients from Vemurafenib Therapy?

Author

Brigitte Dréno, Lucie Peuvrel, Anabelle Brocard, Audrey Vallée, Jean-Michel Nguyen, Gaëlle Quéreux, Marc G. Denis, Amir Khammari, Mélanie Saint-Jean, and Anne-Chantal Knol

Subjects
Proto-Oncogene Proteins B-raf, Oncology, medicine.medical_specialty, Indoles, Skin Neoplasms, Dermatology, Biochemistry, Text mining, Internal medicine, medicine, Humans, Vemurafenib, Melanoma, Protein Kinase Inhibitors, Molecular Biology, Retrospective Studies, Sulfonamides, business.industry, Wild type, Cell Biology, medicine.disease, business, medicine.drug
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10. Sirolimus for Secondary Prevention of Skin Cancer in Kidney Transplant Recipients: 5-Year Results.

Author

Dantal J, Morelon E, Rostaing L, Goffin E, Brocard A, Tromme I, Broeders N, Del Marmol V, Chatelet V, Dompmartin A, Kessler M, Serra A, Hofbauer GFL, Kamar N, Pouteil-Noble C, Kanitakis J, Roux A, Decullier E, and Euvrard S

Subjects
Calcineurin Inhibitors adverse effects, Carcinoma, Squamous Cell prevention & control, Humans, Kidney Transplantation, Secondary Prevention methods, Skin Neoplasms prevention & control, Transplant Recipients, Carcinoma, Squamous Cell immunology, Immunocompromised Host drug effects, Immunosuppressive Agents therapeutic use, Sirolimus therapeutic use, Skin Neoplasms immunology
Abstract

Purpose Transplant recipients who develop cutaneous squamous cell carcinomas are at high risk for multiple subsequent skin cancers. Sirolimus has been shown to reduce the occurrence of secondary skin cancers, but no study included a follow-up exceeding 2 years. We extended at 5 years the TUMORAPA randomized trial of sirolimus-based immunosuppressive regimen versus calcineurin inhibitor-based immunosuppression. Methods Kidney transplant recipients receiving calcineurin inhibitors who had at least one cutaneous squamous cell carcinoma were randomly assigned to receive sirolimus as a substitute for calcineurin inhibitors (n = 64) or to maintain their initial treatment (n = 56). The primary end point was survival free of squamous cell carcinoma at 5 years. Secondary end points included the occurrence of other skin cancers, renal function, patient and graft survival, and treatment tolerance. Results Survival free of cutaneous squamous cell carcinoma was significantly longer in the sirolimus group than in the calcineurin inhibitor group ( P = .007). In the sirolimus group, the number of patients with new skin cancers was significantly lower compared with the calcineurin inhibitor group: 22% versus 59% for squamous cell carcinomas ( P < .001), 34% versus 66% for other skin cancers ( P < .001), and 20% versus 37.5% for basal cell carcinomas ( P < .05). Kidney graft function, patients, and graft survival were similar in both groups. In the sirolimus group, the mean number of serious adverse effects per patient decreased from 1.16 during the first 2 years, to 0.83 between years 2 and 5. Conclusion In kidney transplant recipients with previous cutaneous squamous cell carcinomas, the antitumoral effect of conversion from calcineurin inhibitors to sirolimus was maintained at 5 years, and sirolimus tolerance was satisfactory.

Published
2018
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