RESUMO
We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.
Assuntos
Transferência Adotiva , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Vacinas Anticâncer/administração & dosagem , Células T de Memória , Mieloma Múltiplo , Vacinação , Autoenxertos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/transplante , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/transplante , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Feminino , Hemocianinas/administração & dosagem , Hemocianinas/imunologia , Humanos , Masculino , Células T de Memória/imunologia , Células T de Memória/transplante , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/terapia , Taxa de Sobrevida , Transplante AutólogoRESUMO
A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).
Assuntos
Antígenos CD19/metabolismo , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Adulto , Medula Óssea/imunologia , Medula Óssea/patologia , Feminino , Humanos , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Indução de Remissão , Transplante AutólogoRESUMO
BACKGROUND: Multiple myeloma is usually fatal due to serial relapses that become progressively refractory to therapy. CD19 is typically absent on the dominant multiple myeloma cell population but may be present on minor subsets with unique myeloma-propagating properties. To target myeloma-propagating cells, we clinically evaluated autologous T cells transduced with a chimeric antigen receptor (CAR) against CD19 (CTL019). METHODS: Subjects received CTL019 following salvage high-dose melphalan and autologous stem cell transplantation (ASCT). All subjects had relapsed/refractory multiple myeloma and had previously undergone ASCT with less than 1 year progression-free survival (PFS). RESULTS: ASCT + CTL019 was safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome. Two of 10 subjects exhibited significantly longer PFS after ASCT + CTL019 compared with prior ASCT (479 vs. 181 days; 249 vs. 127 days). Correlates of favorable clinical outcome included peak CTL019 frequency in bone marrow and emergence of humoral and cellular immune responses against the stem-cell antigen Sox2. Ex vivo treatment of primary myeloma samples with a combination of CTL019 and CAR T cells against the plasma cell antigen BCMA reliably inhibited myeloma colony formation in vitro, whereas treatment with either CAR alone inhibited colony formation inconsistently. CONCLUSION: CTL019 may improve duration of response to standard multiple myeloma therapies by targeting and precipitating secondary immune responses against myeloma-propagating cells. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02135406. FUNDING: Novartis, NIH, Conquer Cancer Foundation.
Assuntos
Antígenos CD19/imunologia , Imunoterapia Adotiva/métodos , Melfalan/uso terapêutico , Mieloma Múltiplo/tratamento farmacológico , Receptores de Antígenos de Linfócitos T/uso terapêutico , Idoso , Antígeno de Maturação de Linfócitos B/imunologia , Terapia Combinada/métodos , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunidade Celular/efeitos dos fármacos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Agonistas Mieloablativos/uso terapêutico , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/imunologia , Fatores de Transcrição SOXB1/imunologia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Transplante Autólogo , Resultado do TratamentoRESUMO
Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.
Assuntos
Antígenos de Neoplasias/imunologia , Proteínas de Membrana/imunologia , Mieloma Múltiplo/terapia , Receptores de Antígenos de Linfócitos T/fisiologia , Linfócitos T/imunologia , Idoso , Antígenos de Neoplasias/genética , Antígenos de Superfície/genética , Antígenos de Superfície/imunologia , Feminino , Engenharia Genética , Humanos , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Sindecana-1/análiseRESUMO
PURPOSE: Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells. EXPERIMENTAL DESIGN: In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant. RESULTS: T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%). CONCLUSIONS: A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
Assuntos
Antígenos de Neoplasias/imunologia , Carboximetilcelulose Sódica/análogos & derivados , Imunoterapia Adotiva , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/terapia , Proteínas de Neoplasias/imunologia , Poli I-C/imunologia , Polilisina/análogos & derivados , Linfócitos T/imunologia , Adulto , Idoso , Vacinas Anticâncer/imunologia , Feminino , Transplante de Células-Tronco Hematopoéticas , Humanos , Imunização , Imunoterapia Adotiva/efeitos adversos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/diagnóstico , Mieloma Múltiplo/mortalidade , Polilisina/imunologia , Transplante Autólogo , Resultado do TratamentoRESUMO
OBJECTIVES: The principal aims of this study were to evaluate the extent to which patients completed, understood, and were satisfied with the Health Background Questionnaire for Pain (HBQ-P), a health and pain history questionnaire that includes a modification of the Medical Outcome Study Short Form-36, the Treatment Outcomes in Pain Survey, and to examine the degree to which the questionnaire produced reliable and valid responses. A secondary aim was to determine the length of time for a physician to complete the Clinician Evaluation Form for Pain (CEF-P), a brief questionnaire designed to obtain key elements resulting from clinical assessment and management decisions. METHODS: This cross-sectional study utilized data from consecutive new patients seen from January to December 2001 in Drexel University College of Medicine's Pain Medicine and Comprehensive Rehabilitation Center at Graduate Hospital in Philadelphia, PA. The HBQ-P and an accompanying brief satisfaction inventory were completed at home by the patient prior to the individual's initial office visit. The CEF-P was completed by the physician after seeing the patient. RESULTS: Ten of 11 comparisons of patient responses to similar questions on the HBQ-P showed significant consistency. Of eight comparisons between the CEF-P and HBQ-P, two pain duration comparisons showed moderate agreement and one depression comparison showed significant association. Patients consistently had difficulty in answering six single questions and two question sets. Overall patient satisfaction was high. The mean time for the physician to complete the CEF-P was 90 seconds. CONCLUSIONS: Analyses indicate patient responses to similar HBQ-P questions have sufficient reliability to support the use of the Health Background Questionnaire for clinically related data collection and for outcome evaluation of treatments for chronic and recurring pain. The consistently missed questions on the HBQ-P should be revised.