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CAR-T cell therapies have been successful in treating numerous hematologic malignancies as the T cell can be engineered to target a specific antigen associated with the disease. However, translating CAR-T cell therapies for solid cancers is proving more challenging due to the lack of truly tumor-associated antigens and the high risk of off-target toxicities. To combat this, numerous synthetic biology mechanisms are being incorporated to create safer and more specific CAR-T cells that can be spatiotemporally controlled with increased precision. Here, we seek to summarize and analyze the advancements for CAR-T cell therapies with respect to clinical implementation, from the perspective of synthetic biology and immunology. This review should serve as a resource for further investigation and growth within the field of personalized cellular therapies.
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Imunoterapia Adotiva , Neoplasias , Receptores de Antígenos Quiméricos , Biologia Sintética , Linfócitos T , Humanos , Neoplasias/terapia , Neoplasias/imunologia , Biologia Sintética/métodos , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Linfócitos T/imunologia , Antígenos de Neoplasias/imunologiaRESUMO
BACKGROUND AIMS: The field of cell and gene therapy in oncology has moved rapidly since 2017 when the first cell and gene therapies, Kymriah followed by Yescarta, were approved by the Food and Drug Administration in the United States, followed by multiple other countries. Since those approvals, several new products have gone on to receive approval for additional indications. Meanwhile, efforts have been made to target different cancers, improve the logistics of delivery and reduce the cost associated with novel cell and gene therapies. Here, we highlight various cell and gene therapy-related technologies and advances that provide insight into how these new technologies will speed the translation of these therapies into the clinic. CONCLUSIONS: In this review, we provide a broad overview of the current state of cell and gene therapy-based approaches for cancer treatment - discussing various effector cell types and their sources, recent advances in both CAR and non-CAR genetic modifications, and highlighting a few promising approaches for increasing in vivo efficacy and persistence of therapeutic drug products.
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Imunoterapia Adotiva , Neoplasias , Humanos , Neoplasias/genética , Neoplasias/terapia , Terapia Genética , Edição de GenesRESUMO
There is considerable interest in the next generation of personalized medicine, especially cell and gene therapy products such as chimeric antigen receptor T cells (CAR-Ts). Unlike other small molecules or pharmacologic drugs, most existing cell or cell-based gene therapy products (CGTs) require apheresis collection of the patient or donor, subsequent manufacture of the product, and final shipment of the product to the clinical site for infusion. Whereas traditional pharmaceutical drugs have involved the drug sponsor and the clinical site and clinical pharmacy, this new manufacturing paradigm has evolved, in many cases, to include an apheresis center, a cell processing lab, the sponsor's manufacturing facility, and a clinical site with or without a pharmacy. Here we report the results of a survey of current practices handling investigational CGTs conducted by the Immuno-Gene Therapy committee of the International Society of Cell and Gene Therapy.
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Farmácia , Receptores de Antígenos Quiméricos , Terapia Genética , Hospitais , Humanos , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos/genéticaRESUMO
The liver is an immunologically active organ with a tolerogenic microenvironment at a quiescent state. The immunoregulatory properties of the liver appear to be retained after transplantation because liver allografts can reduce alloresponses against other organs that are simultaneously transplanted. Mechanisms of this phenomenon remain unknown. Given the known immunomodulatory properties of mesenchymal stromal cells (MSCs), we hypothesized that liver mesenchymal stromal cells (L-MSCs) are superior immunomodulators and contribute to liver-mediated tolerance. L-MSCs, generated from human liver allograft biopsies, were compared with adipose mesenchymal stromal cells (A-MSCs) and bone marrow mesenchymal stromal cells (BM-MSCs). Trilineage differentiation of L-MSCs was confirmed by immunohistochemistry. Comparative phenotypic analyses were done by flow cytometry and transcriptome analyses by RNA sequencing in unaltered cell cultures. The in vitro functional analyses were performed using alloreactive T cell proliferation assays. The transcriptome analysis showed that the L-MSCs are different than the A-MSCs and BM-MSCs, with significant enrichment of genes and gene sets associated with immunoregulation. Compared with the others, L-MSCs were found to express higher cell surface levels of several select immunomodulatory molecules. L-MSCs (versus A-MSCs/BM-MSCs) inhibited alloreactive T cell proliferation (22.7% versus 56.4%/58.7%, respectively; P < 0.05) and reduced the frequency of interferon ɤ-producing T cells better than other MSCs (52.8% versus 94.4%/155.4%; P < 0.05). The antiproliferative impact of L-MSCs was not dependent on cell-to-cell contact, could be reversed incompletely by blocking programmed death ligand 1, and required a higher concentration of the competitive inhibitor of indoleamine 2,3-dioxygenase for complete reversal. In conclusion, L-MSCs appear to be uniquely well-equipped immunomodulatory cells, and they are more potent than A-MSCs and BM-MSCs in that capacity, which suggests that they may contribute to liver-induced systemic tolerance.
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Transplante de Fígado , Células-Tronco Mesenquimais , Células da Medula Óssea , Diferenciação Celular , Proliferação de Células , Células Cultivadas , Humanos , Imunomodulação , FígadoRESUMO
Kidney allografts of patients who undergo simultaneous liver-kidney transplantation incur less immune-mediated injury, and retain better function compared to other kidney allografts. To characterize the host alloimmune responses in 28 of these patients, we measured the donor-specific alloresponsiveness and phenotypes of peripheral blood cells after the first year. These values were then compared to those of 61 similarly immunosuppressed recipients of a solitary kidney or 31 recipients of liver allografts. Four multicolor, non-overlapping flow cytometry protocols were used to assess the immunophenotypes. Mixed cell cultures with donor or third party cells were used to measure cell proliferation and interferon gamma production. Despite a significant overlap, simultaneous liver-kidney transplant recipients had a lower overall frequency of circulating CD8+, activated CD4+ and effector memory T cells, compared to solitary kidney transplant recipients. Simultaneous liver-kidney transplant recipient T cells had a significantly lower proliferative response to the donor cells compared to solitary kidney recipients (11.9 vs. 42.9%), although their response to third party cells was unaltered. The frequency of interferon gamma producing alloreactive T cells in simultaneous liver-kidney transplant recipients was significantly lower than that of solitary kidney transplant recipients. Flow cytometric analysis of the mixed cultures demonstrated that both alloreactive CD4+ and CD8+ compartments of the simultaneous liver-kidney transplant recipient circulating blood cells were smaller. Thus, the phenotypic and functional characteristics of the circulating blood cells of the simultaneous liver-kidney transplant recipients resembled those of solitary liver transplant recipients, and appear to be associated with donor-specific hypo-alloresponsiveness.
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Antígenos HLA-A/imunologia , Histocompatibilidade , Isoanticorpos/imunologia , Transplante de Rim , Transplante de Fígado , Ativação Linfocitária , Subpopulações de Linfócitos T/imunologia , Adulto , Idoso , Aloenxertos , Biomarcadores/sangue , Células Cultivadas , Feminino , Rejeição de Enxerto/imunologia , Sobrevivência de Enxerto , Humanos , Imunossupressores/uso terapêutico , Isoanticorpos/sangue , Transplante de Rim/efeitos adversos , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fenótipo , Fatores de Risco , Subpopulações de Linfócitos T/metabolismo , Fatores de Tempo , Resultado do TratamentoRESUMO
CASE REPORT: A 50-year-old male with T-cell lymphoma presented for autologous peripheral blood stem cell transplantation. After granulocyte-colony-stimulating factor (G-CSF) mobilization, his peripheral blood CD34+ cell count was 166 × 10(6) /L on the day before collection, which predicted a high yield of CD34+ cells in the apheresis product. The first two collections had yields much lower than expected, triggering an investigation and changes to the apheresis collection methods since mobilization appeared adequate from the peripheral CD34+ values. RESULTS: Changes to the apheresis collection variables and instrumentation did not improve the yields in the next three collections. The laboratory investigation demonstrated that there was an interfering substance in the patient's plasma that was causing falsely high peripheral blood CD34+ cell values and that the low CD34+ cell yields in the collections were consistent with the actual peripheral blood CD34+ cell value. Based on this finding and after discussion with the clinical service, the patient then received plerixafor to increase the number of circulating CD34+ cells before Collections 6 and 7. The patient went on to achieve the target CD34+ cell dose and subsequently underwent a successful autologous transplant with full hematopoietic engraftment. CONCLUSION: This case demonstrates the importance of timely and critical review of laboratory results in the context of the specific patient. This case exemplifies how diligent review of laboratory results and open communication among the various teams can positively affect patient outcomes.
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Antígenos CD34/metabolismo , Remoção de Componentes Sanguíneos , Fator Estimulador de Colônias de Granulócitos/metabolismo , Transplante de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) specific T-cells and neutralizing antibodies (nAbs) during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers. METHODS: Eighteen healthy participants completed a 20-min bout of graded cycling exercise before and/or after receiving a COVID-19 vaccine. All major leukocyte subtypes were enumerated before, during, and after exercise by flow cytometry, and immune responses to SARS-CoV-2 were determined using whole blood peptide stimulation assays, T-cell receptor (TCR)-ß sequencing, and SARS-CoV-2 nAb serology. RESULTS: COVID-19 vaccination had no effect on the mobilization or egress of major leukocyte subsets in response to intensity-controlled graded exercise. However, non-infected participants had a significantly reduced mobilization of CD4+ and CD8+ naive T-cells, as well as CD4+ central memory T-cells, after vaccination (synthetic immunity group); this was not seen after vaccination in those with prior SARS-CoV-2 infection (hybrid immunity group). Acute exercise after vaccination robustly mobilized SARS-CoV-2 specific T-cells to blood in an intensity-dependent manner. Both groups mobilized T-cells that reacted to spike protein; however, only the hybrid immunity group mobilized T-cells that reacted to membrane and nucleocapsid antigens. nAbs increased significantly during exercise only in the hybrid immunity group. CONCLUSION: These data indicate that acute exercise mobilizes SARS-CoV-2 specific T-cells that recognize spike protein and increases the redistribution of nAbs in individuals with hybrid immunity.
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COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , Linfócitos T , Glicoproteína da Espícula de Coronavírus , Exercício FísicoRESUMO
Immunosuppression is a known risk factor for B-cell non-Hodgkin lymphoma (NHL), yet mechanisms of tumor-associated immunosuppression remain to be fully characterized. We examined the immunophenotype of 40 NHL patients and 27 age-matched healthy volunteers to better understand systemic immune suppression. NHL peripheral blood mononuclear cells had significantly decreased interferon-γ production and proliferation. This suppression was not the result of regulatory T cells, interleukin-6 or interleukin-10, as these factors were not different between NHL and healthy volunteers (controls). We were able to restore T-cell proliferation by removing NHL monocytes, suggesting that these monocytes are suppressive. This suppression was mediated in part through arginine metabolism as exogenous arginine supplementation partially overcame monocytes' suppression of T-cell proliferation in vitro and NHL patients had elevated arginase I in their plasma. NHL monocytes had impaired STAT1 phosphorylation and interferon-α production to CpG stimulation and a dendritic cell differentiation deficiency. Further studies demonstrated that monocytes from NHL patients had decreased HLA-DR and Tumor necrosis factor-α receptor II (CD120b) expression compared with controls (CD14(+)HLA-DR(low/-)CD120b(low)). Patients with increased ratios of CD14(+)HLA-DR(low/-) monocytes had more aggressive disease and suppressed immune functions. In summary, we report that CD14(+)HLA-DR(low/-) monocytes are a major and multifactorial contributor to systemic immunosuppression in NHL.
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Antígenos HLA-DR/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Linfoma de Células B/imunologia , Monócitos/imunologia , Arginase/genética , Arginase/metabolismo , Arginina/farmacologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citometria de Fluxo , Humanos , Imunofenotipagem , Terapia de Imunossupressão , Interferon-alfa/metabolismo , Interferon gama/metabolismo , Interferon gama/farmacologia , Interleucina-6/farmacologia , Linfoma de Células B/patologia , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosforilação/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Transcrição STAT1/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismoRESUMO
Background: Exploring the immune interface of follicular cell-derived thyroid cancer has prognostic and therapeutic potential. The available literature is lacking for comprehensive immunophenotyping in relation to clinical outcomes. In this study, we identify circulating immunophenotypes associated with thyroid cancer prognosis. Methods: We conducted a pilot observational study of adults with follicular cell-derived thyroid cancer who underwent surgery at our tertiary care referral center and had consented for flow cytometry on peripheral blood collected at the time of thyroidectomy. Results: Of the 32 included subjects, 20 (62%) had well differentiated, 5 (16%) had poorly differentiated, and 7 (22%) had anaplastic thyroid cancer. The most frequent AJCC stage was 4 (59%) and the ATA risk of recurrence category was high (56%). Patients with AJCC stage 3/4 demonstrated fewer circulating mononuclear cells (CD45+), more monocytes (CD14+), fewer total lymphocytes (CD14-), fewer T cells (CD3+), fewer CD4+ T cells, fewer gamma-delta T cells, fewer natural killer (NK) T-like cells, more myeloid-derived suppressor cells (MDSCs; Lin-CD33+HLADR-), and more effector memory T cells but similar CD8+ T cells compared to stage1/2. Immunophenotype comparisons by ATA risk stratification and course of thyroid cancer were comparable to those observed for stage, except for significant differences in memory T cell subtypes. The median follow-up was 58 months. Conclusions: Aggressive follicular cell-derived thyroid cancer either at presentation or during follow-up is associated with down-regulation of the T cell populations specifically CD4+ T cells, gamma-delta T cells, and NK T-like cells but up-regulation of MDSCs and altered memory T cells. These immunophenotypes are potential prognostic biomarkers supporting future investigation for developing targeted immunotherapies against advanced thyroid cancer.
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Adenocarcinoma Folicular , Linfócitos T CD8-Positivos , Neoplasias da Glândula Tireoide , Adulto , Humanos , Prognóstico , Imunofenotipagem , Linfócitos T CD4-PositivosRESUMO
Mesenchymal stem/stromal cells (MSCs) have been carefully examined to have tremendous potential in regenerative medicine. With their immunomodulatory and regenerative properties, MSCs have numerous applications within the clinical sector. MSCs have the properties of multilineage differentiation, paracrine signaling, and can be isolated from various tissues, which makes them a key candidate for applications in numerous organ systems. To accentuate the importance of MSC therapy for a range of clinical indications, this review highlights MSC-specific studies on the musculoskeletal, nervous, cardiovascular, and immune systems where most trials are reported. Furthermore, an updated list of the different types of MSCs used in clinical trials, as well as the key characteristics of each type of MSCs are included. Many of the studies mentioned revolve around the properties of MSC, such as exosome usage and MSC co-cultures with other cell types. It is worth noting that MSC clinical usage is not limited to these four systems, and MSCs continue to be tested to repair, regenerate, or modulate other diseased or injured organ systems. This review provides an updated compilation of MSCs in clinical trials that paves the way for improvement in the field of MSC therapy.
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PURPOSE: Acute exercise redistributes large numbers of memory T cells, which may contribute to enhanced immune surveillance in regular exercisers. It is not known, however, if acute exercise promotes a broad or oligoclonal T-cell receptor (TCR) repertoire or evokes transcriptomic changes in "exercise-responsive" T-cell clones. METHODS: Healthy volunteers completed a graded bout of cycling exercise up to 80% VÌO 2max . DNA was extracted from peripheral blood mononuclear cells collected at rest, during exercise (EX), and 1 h after (+1H) exercise, and processed for deep TCR-ß chain sequencing and tandem single-cell RNA sequencing. RESULTS: The number of unique clones and unique rearrangements was decreased at EX compared with rest ( P < 0.01) and +1H ( P < 0.01). Productive clonality was increased compared with rest ( P < 0.05) and +1H ( P < 0.05), whereas Shannon's Index was decreased compared with rest ( P < 0.05) and +1H ( P < 0.05). The top 10 rearrangements in the repertoire were increased at EX compared with rest ( P < 0.05) and +1H ( P < 0.05). Cross-referencing TCR-ß sequences with a public database (VDJdb) revealed that exercise increased the number of clones specific for the most prevalent motifs, including Epstein-Barr virus, cytomegalovirus, and influenza A. We identified 633 unique exercise-responsive T-cell clones that were mobilized and/or egressed in response to exercise. Among these clones, there was an upregulation in genes related to cell death, cytotoxicity, and activation ( P < 0.05). CONCLUSIONS: Acute exercise promotes an oligoclonal T-cell repertoire by preferentially mobilizing the most dominant clones, several of which are specific to known viral antigens and display differentially expressed genes indicative of cytotoxicity, activation, and apoptosis.
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Infecções por Vírus Epstein-Barr , Linfócitos T , Humanos , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo , Infecções por Vírus Epstein-Barr/metabolismo , Leucócitos Mononucleares/metabolismo , Herpesvirus Humano 4/metabolismo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Células Clonais/metabolismo , Exercício FísicoRESUMO
Background: Every bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia. Methods: Peripheral blood mononuclear cells (PBMCs) were collected from healthy volunteers at rest and at the end of an acute bout of cycling exercise. Flow cytometry and single-cell RNA sequencing was performed to identify phenotypic and transcriptomic differences between resting and exercise-mobilized cells using a targeted gene expression panel curated for human immunology. PBMCs were injected into the tail vein of xenogeneic NSG-IL-15 mice and subsequently challenged with a luciferase tagged chronic myelogenous leukemia cell line (K562). Tumor growth (bioluminescence) and xenogeneic graft-versus-host disease (GvHD) were monitored bi-weekly for 40-days. Results: Exercise preferentially mobilized NK-cell, CD8+ T-cell and monocyte subtypes with a differentiated and effector phenotype, without significantly mobilizing CD4+ regulatory T-cells. Mobilized effector lymphocytes, particularly effector-memory CD8+ T-cells and NK-cells, displayed differentially expressed genes and enriched gene sets associated with anti-tumor activity, including cytotoxicity, migration/chemotaxis, antigen binding, cytokine responsiveness and alloreactivity (e.g. graft-versus-host/leukemia). Mice receiving exercise-mobilized PBMCs had lower tumor burden and higher overall survival (4.14E+08 photons/s and 47%, respectively) at day 40 compared to mice receiving resting PBMCs (12.1E+08 photons/s and 22%, respectively) from the same donors (p<0.05). Human immune cell engraftment was similar for resting and exercise-mobilized DLI. However, when compared to non-tumor bearing mice, K562 increased the expansion of NK-cell and CD3+/CD4-/CD8- T-cells in mice receiving exercise-mobilized but not resting lymphocytes, 1-2 weeks after DLI. No differences in GvHD or GvHD-free survival was observed between groups either with or without K562 challenge. Conclusion: Exercise in humans mobilizes effector lymphocytes with an anti-tumor transcriptomic profile and their use as DLI extends survival and enhances the graft-versus-leukemia (GvL) effect without exacerbating GvHD in human leukemia bearing xenogeneic mice. Exercise may serve as an effective and economical adjuvant to increase the GvL effects of allogeneic cell therapies without intensifying GvHD.
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Doença Enxerto-Hospedeiro , Leucemia , Humanos , Camundongos , Animais , Leucócitos Mononucleares , Transcriptoma , Células Matadoras Naturais , Camundongos Endogâmicos , Leucemia/genética , Leucemia/terapiaRESUMO
BACKGROUND: Glioblastoma is an extraordinarily heterogeneous tumor, yet the current treatment paradigm is a "one size fits all" approach. Hundreds of glioblastoma clinical trials have been deemed failures because they did not extend median survival, but these cohorts are comprised of patients with diverse tumors. Current methods of assessing treatment efficacy fail to fully account for this heterogeneity. METHODS: Using an image-based modeling approach, we predicted T-cell abundance from serial MRIs of patients enrolled in the dendritic cell (DC) vaccine clinical trial. T-cell predictions were quantified in both the contrast-enhancing and non-enhancing regions of the imageable tumor, and changes over time were assessed. RESULTS: A subset of patients in a DC vaccine clinical trial, who had previously gone undetected, were identified as treatment responsive and benefited from prolonged survival. A mere two months after initial vaccine administration, responsive patients had a decrease in model-predicted T-cells within the contrast-enhancing region, with a simultaneous increase in the T2/FLAIR region. CONCLUSIONS: In a field that has yet to see breakthrough therapies, these results highlight the value of machine learning in enhancing clinical trial assessment, improving our ability to prospectively prognosticate patient outcomes, and advancing the pursuit towards individualized medicine.
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CD3+/CD56+ Natural killer (NK) cell-like T-cells (NKT-like cells) represent <5% of blood lymphocytes, display a cytotoxic phenotype, and can kill various cancers. NKT-like cells can be expanded ex vivo into cytokine-induced killer (CIK) cells, however this therapeutic cell product has had mixed results against hematological malignancies in clinical trials. The aim of this study was to determine if NKT-like cells mobilized during acute cycling exercise could be used to generate more potent anti-tumor CIK cells from healthy donors. An acute exercise bout increased NKT-like cell numbers in blood 2-fold. Single cell RNA sequencing revealed that exercise mobilized NKT-like cells have an upregulation of genes and transcriptomic programs associated with enhanced anti-tumor activity, including cytotoxicity, cytokine responsiveness, and migration. Exercise, however, did not augment the ex vivo expansion of CIK cells or alter their surface phenotypes after 21-days of culture. CIK cells expanded at rest, during exercise (at 60% and 80% VO2max) or after (1h post) were equally capable of killing leukemia, lymphoma, and multiple myeloma target cells with and without cytokine (IL-2) and antibody (OKT3) priming in vitro. We conclude that acute exercise in healthy donors mobilizes NKT-like cells with an upregulation of transcriptomic programs involved in anti-tumor activity, but does not augment the ex vivo expansion of CIK cells.
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Células Matadoras Induzidas por Citocinas , Neoplasias , Citotoxicidade Imunológica , Exercício Físico , Humanos , Interleucina-2/farmacologia , Muromonab-CD3/farmacologia , TranscriptomaRESUMO
Background: Glioblastoma (GBM) has poor prognosis despite aggressive treatment. Dendritic cell (DC) vaccines are promising, but widespread clinical use has not been achieved, possibly reflecting manufacturing issues of antigen choice and DC potency. We previously optimized vaccine manufacture utilizing allogeneic human GBM tumor cell lysate and potent, mature autologous DCs. Here, we report a phase I study using this optimized DC vaccine in combination with standard therapy. Methods: Following surgical resection and radiation with concurrent temozolomide (TMZ), newly diagnosed adult GBM patients received intradermal DC vaccines plus TMZ. Primary endpoints were safety and feasibility. Immune and treatment responses were recorded. Results: Twenty-one patients were enrolled in this study. One progressed between leukapheresis and vaccine manufacture. Twenty patients received treatment per protocol. Vaccine doses (≥15) were generated following a single leukapheresis for each patient. No dose-limiting vaccine toxicities were encountered. One patient had symptomatic, histologically proven pseudoprogression. Median progression-free survival was 9.7 months. Median overall survival was 19 months. Overall survival was 25% at 2 years and 10% at 4 years. One patient remains progression-free 5 years after enrollment. Specific CD8 T-cell responses for the tumor-associated antigen gp100 were seen post-vaccination. Patients entered the trial with a leukocyte deficit compared to healthy donors which partly normalized over the course of therapy. Conclusions: This vaccine platform is safe and highly feasible in combination with standard therapy for newly diagnosed patients. Imaging, histological, survival, and immunological data suggest a positive biological response to therapy that warrants further investigation.
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The remarkable success of cancer immunotherapies has provided new hope to cancer patients. Unfortunately, a significant proportion of patients remain unable to respond to immunotherapy or maintain durable clinical responses. The lack of objective responses likely results from profound immune dysfunction often observed in patients with cancer. There is substantial evidence that exercise and physical activity can reduce incidence and improve outcomes in cancer patients. As the immune system is highly responsive to exercise, one potential avenue to improve immune function is through exercise and physical activity. A single event of dynamic exercise results in the substantial mobilization of leukocytes with increased functional capacities into the circulation. Chronic, or long-term, exercise leads to higher physical fitness in terms of greater cardiorespiratory function and/or muscle strength and endurance. High aerobic capacity, as measured by maximal oxygen uptake, has been associated with the reduction of dysfunctional T cells and improvements in the abundance of some T cell populations. To be sure, however, the mechanisms of exercise-mediated immune changes are both extensive and diverse. Here, we examine the evidence and theorize how acute and chronic exercise could be used to improve responses to cancer immunotherapies including immune checkpoint inhibitors, dendritic cell vaccines, natural killer cell therapies, and adoptive T cell therapies such as chimeric antigen receptor (CAR) T cells. Although the parameters of optimal exercise to yield defined outcomes remain to be determined, the available current data provide a compelling justification for additional human studies and clinical trials investigating the adjuvant use of exercise in immuno-oncology.
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Exercício Físico/imunologia , Sistema Imunitário/fisiopatologia , Imunoterapia/métodos , Feminino , HumanosRESUMO
OBJECTIVES: Inhibitors to the checkpoint proteins cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are becoming widely used in cancer treatment. However, a lack of understanding of the patient response to treatment limits accurate identification of potential responders to immunotherapy. METHODS: In this study, we assessed the expression of PD-1 and CTLA-4 on 19 leucocyte populations in the peripheral blood of 74 cancer patients. A reference data set for PD-1 and CTLA-4 was established for 40 healthy volunteers to determine the normal expression patterns for these checkpoint proteins. RESULTS: Unsupervised hierarchical clustering found four immune profiles shared across the solid tumor types, while chronic lymphocytic leukaemia patients had an immune profile largely unique to them. Furthermore, we measured these leucocyte populations on an additional cohort of 16 cancer patients receiving the PD-1 inhibitor pembrolizumab in order to identify differences between responders and non-responders, as well as compared to healthy volunteers (n = 20). We observed that cancer patients had pre-treatment PD-1 and CTLA-4 expression on their leucocyte populations at different levels compared to healthy volunteers and identified two leucocyte populations positive for CTLA-4 that had not been previously described. We found higher levels of PD-1+ CD3+ CD4- CD8- cells in patients with progressive disease and have identified it as a potential biomarker of response, as well as identifying other significant differences in phenotypes between responders and non-responders. CONCLUSION: These results are suggestive that categorisation of patients based on immune profiles may differentiate responders from non-responders to immunotherapy for solid tumors.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Transferência Adotiva/métodos , Neoplasias dos Ductos Biliares/terapia , Ductos Biliares Intra-Hepáticos , Linfócitos T CD4-Positivos/imunologia , Colangiocarcinoma/terapia , Linfócitos do Interstício Tumoral/transplante , Células Th1/transplante , Feminino , HumanosRESUMO
Background: Immune checkpoint inhibitors (ICIs) frequently cause thyroid dysfunction but their underlying mechanism remains unclear. We have previously demonstrated increased circulating natural killer (NK) cells and human leukocyte antigen (HLA)-DR surface expression on inflammatory intermediate CD14+CD16+ monocytes in programmed cell death protein-1 (PD-1) inhibitor-treated patients. This study characterizes intrathyroidal and circulating immune cells and class II HLA in ICI-induced thyroiditis. Methods: This is a single-center prospective cohort study of 10 patients with ICI-induced thyroiditis by flow cytometry of thyroid fine needle aspirates (n = 9) and peripheral blood (n = 7) as compared with healthy thyroid samples (n = 5) and healthy volunteer blood samples (n = 44); HLA class II was tested in n = 9. Results: ICI-induced thyroiditis samples demonstrated overall increased T lymphocytes (61.3% vs. 20.1%, p = 0.00006), CD4-CD8- T lymphocytes (1.9% vs. 0.7%, p = 0.006), and, as a percent of T lymphocytes, increased CD8+T lymphocytes (38.6% vs. 25.7%; p = 0.0259) as compared with healthy thyroid samples. PD-1 inhibitor-induced thyroiditis had increased CD4+PD1+ T lymphocytes (40.4% vs. 0.8%; p = 0.021) and CD8+PD1+ T lymphocytes (28.8% vs. 1.5%; p = 0.038) in the thyroid compared with the blood. Circulating NK cells, certain T lymphocytes (CD4+CD8+, CD4-CD8- T, gamma-delta), and intermediate monocytes were increased in ICI-induced thyroiditis. Six patients typed as HLA-DR4-DR53 and three as HLA-DR15. Conclusions: ICI-induced thyroiditis is a T lymphocyte-mediated process with intra-thyroidal predominance of CD8+ and CD4-CD8- T lymphocytes. The HLA haplotypes may be involved but need further evaluation. These findings expand the limited understanding of ICI-induced thyroiditis, which could be further translated to guide immunomodulatory therapies for advanced thyroid cancer.