RESUMO
Chimeric antigen receptor (CAR) T cell therapy has achieved remarkable success in hematological malignancies but remains ineffective in solid tumors, due in part to CAR T cell exhaustion in the solid tumor microenvironment. To study dysfunction of mesothelin-redirected CAR T cells in pancreatic cancer, we establish a robust model of continuous antigen exposure that recapitulates hallmark features of T cell exhaustion and discover, both in vitro and in CAR T cell patients, that CAR dysregulation is associated with a CD8+ T-to-NK-like T cell transition. Furthermore, we identify a gene signature defining CAR and TCR dysregulation and transcription factors, including SOX4 and ID3 as key regulators of CAR T cell exhaustion. Our findings shed light on the plasticity of human CAR T cells and demonstrate that genetic downmodulation of ID3 and SOX4 expression can improve the efficacy of CAR T cell therapy in solid tumors by preventing or delaying CAR T cell dysfunction.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Imunoterapia Adotiva/métodos , Neoplasias Pancreáticas/terapia , Receptores de Antígenos Quiméricos/imunologia , Animais , Linfócitos T CD8-Positivos/citologia , Linhagem Celular Tumoral , Células HEK293 , Humanos , Proteínas Inibidoras de Diferenciação/imunologia , Masculino , Camundongos , Camundongos Knockout , Camundongos Nus , Camundongos SCID , Proteínas de Neoplasias/imunologia , Fatores de Transcrição SOXC/imunologiaRESUMO
Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 1012 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later. Twelve patients participated after appropriate informed consent. Vector-related adverse events were minimal. Immune biomarkers were evaluated in tumor and blood before and after GMCI. Significantly increased infiltration of CD8+ T cells was found in resected tumors. Expression of activation, inhibitory, and proliferation markers, such as human leukocyte antigen (HLA)-DR, CD38, Ki67, PD-1, CD39, and CTLA-4, were significantly increased in both the tumor and peripheral CD8+ T cells. Thus, intratumoral AdV-tk injection into non-small-cell lung cancer (NSCLC) proved safe and feasible, and it effectively induced CD8+ T cell activation. These data provide a foundation for additional clinical trials of GMCI for lung cancer patients with potential benefit if combined with other immune therapies.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/terapia , Terapia Genética , Imunoterapia/métodos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Adenoviridae/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Citotoxicidade Imunológica , Terapia Genética/métodos , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Neoplasias Pulmonares/patologia , Terapia Neoadjuvante , Timidina Quinase/genéticaRESUMO
Chimeric antigen receptor (CAR)-modified T cells are endowed with novel antigen specificity and are most often administered to patients without an engineered mechanism to control the CAR T cells once infused. "Suicide switches" such as the small molecule-controlled, inducible caspase-9 (iCas9) system afford the ability to selectively eliminate engineered T cells; however, these approaches are designed for all-or-none, irreversible termination of an ongoing immune response. In order to permit reversible and adjustable modulation, we have created a CAR that is capable of on-demand downregulation by fusing the CAR to a previously developed ligand-induced degradation (LID) domain. Addition of a small molecule ligand triggers exposure of a cryptic degron within the LID domain, resulting in proteasomal degradation of the CAR-LID fusion protein and loss of CAR on the surface of T cells. This fusion construct allowed for reversible and "tunable" inhibition of CAR T cell activity in vitro. Delivery of the triggering molecule in CAR-LID-treated tumor-bearing mice temporarily reduced CAR activity through modulation of CAR surface expression. The ability to more flexibly modulate CAR T cell expression through a small molecule provides a platform for controlling possible adverse side effects, as well as preclinical investigations of CAR T cell biology.
Assuntos
Morfolinas/química , Neoplasias/terapia , Receptores de Antígenos Quiméricos/metabolismo , Proteínas Recombinantes de Fusão/química , Bibliotecas de Moléculas Pequenas/administração & dosagem , Linfócitos T/transplante , Animais , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Humanos , Imunoterapia Adotiva , Ligantes , Camundongos , Transplante de Neoplasias , Neoplasias/imunologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Domínios Proteicos , Proteólise , Receptores de Antígenos Quiméricos/química , Proteínas Recombinantes de Fusão/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Linfócitos T/citologia , Linfócitos T/metabolismoRESUMO
Each year, more than 700,000 people undergo cancer surgery in the United States. However, more than 40% of those patients develop recurrences and have a poor outcome. Traditionally, the medical community has assumed that recurrent tumors arise from selected tumor clones that are refractory to therapy. However, we found that tumor cells have few phenotypical differences after surgery. Thus, we propose an alternative explanation for the resistance of recurrent tumors. Surgery promotes inhibitory factors that allow lingering immunosuppressive cells to repopulate small pockets of residual disease quickly. Recurrent tumors and draining lymph nodes are infiltrated with M2 (CD11b(+)F4/80(hi)CD206(hi) and CD11b(+)F4/80(hi)CD124(hi)) macrophages and CD4(+)Foxp3(+) regulatory T cells. This complex network of immunosuppression in the surrounding tumor microenvironment explains the resistance of tumor recurrences to conventional cancer vaccines despite small tumor size, an intact antitumor immune response, and unaltered cancer cells. Therapeutic strategies coupling antitumor agents with inhibition of immunosuppressive cells potentially could impact the outcomes of more than 250,000 people each year.
Assuntos
Vacinas Anticâncer/imunologia , Recidiva Local de Neoplasia/imunologia , Neoplasias/imunologia , Microambiente Tumoral/imunologia , Animais , Antígenos de Diferenciação/imunologia , Antígenos de Diferenciação/metabolismo , Antígeno CD11b/imunologia , Antígeno CD11b/metabolismo , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-4/imunologia , Subunidade alfa de Receptor de Interleucina-4/metabolismo , Estimativa de Kaplan-Meier , Lectinas Tipo C/imunologia , Lectinas Tipo C/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Receptor de Manose , Lectinas de Ligação a Manose/imunologia , Lectinas de Ligação a Manose/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias/patologia , Neoplasias/cirurgia , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Falha de Tratamento , Vacinação/métodosAssuntos
Neoplasias Pulmonares , Derrame Pleural Maligno , Derrame Pleural , Amigos , Humanos , Interleucina-17RESUMO
The clinical benefits of tumor-targeting antibodies (tAb) are modest in solid human tumors. The efficacy of many tAbs is dependent on Fc receptor (FcR)-expressing leukocytes that bind Fc fragments of tAb. Tumor-associated macrophages (TAM) and neutrophils (TAN) represent the majority of FcR+ effectors in solid tumors. A better understanding of the mechanisms by which TAMs and TANs regulate tAb response could help improve the efficacy of cancer treatments. Here, we found that myeloid effectors interacting with tAb-opsonized lung cancer cells used antibody-dependent trogocytosis (ADT) but not antibody-dependent phagocytosis. During this process, myeloid cells "nibbled off" tumor cell fragments containing tAb/targeted antigen (tAg) complexes. ADT was only tumoricidal when the tumor cells expressed high levels of tAg and the effectors were present at high effector-to-tumor ratios. If either of these conditions were not met, which is typical for solid tumors, ADT was sublethal. Sublethal ADT, mainly mediated by CD32hiCD64hi TAM, led to two outcomes: (i) removal of surface tAg/tAb complexes from the tumor that facilitated tumor cell escape from the tumoricidal effects of tAb; and (ii) acquisition of bystander tAgs by TAM with subsequent cross-presentation and stimulation of tumor-specific T-cell responses. CD89hiCD32loCD64lo peripheral blood neutrophils (PBN) and TAN stimulated tumor cell growth in the presence of the IgG1 anti-EGFR Ab cetuximab; however, IgA anti-EGFR Abs triggered the tumoricidal activity of PBN and negated the stimulatory effect of TAN. Overall, this study provides insights into the mechanisms by which myeloid effectors mediate tumor cell killing or resistance during tAb therapy. SIGNIFICANCE: The elucidation of the conditions and mechanisms by which human FcR+ myeloid effectors mediate cancer cell resistance and killing during antibody treatment could help develop improved strategies for treating solid tumors.
Assuntos
Neoplasias , Neutrófilos , Humanos , Neutrófilos/metabolismo , Macrófagos Associados a Tumor/metabolismo , Trogocitose , Citotoxicidade Celular Dependente de Anticorpos , Fagocitose , Neoplasias/patologia , Receptores Fc , Antígenos de NeoplasiasRESUMO
Since previous work using a nonreplicating adenovirus-expressing mouse interferon-ß (Ad.mIFNß) showed promising preclinical activity, we postulated that a vector-expressing IFNß at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNß (VV.mIFNß) was tested. VV.mIFNß-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNß had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFNß vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.
Assuntos
Imunoterapia/métodos , Interferon beta/metabolismo , Vaccinia virus/genética , Animais , Linhagem Celular Tumoral , Feminino , Interferon beta/genética , Neoplasias Pulmonares/terapia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Vaccinia virus/imunologia , Replicação Viral/genética , Replicação Viral/fisiologiaRESUMO
Chimeric antigen receptor (CAR) T cells demonstrate remarkable success in treating hematological malignancies, but their effectiveness in non-hematopoietic cancers remains limited. This study proposes enhancing CAR T cell function and localization in solid tumors by modifying the epigenome governing tissue-residency adaptation and early memory differentiation. We identify that a key factor in human tissue-resident memory CAR T cell (CAR-TRM) formation is activation in the presence of the pleotropic cytokine, transforming growth factor ß (TGF-ß), which enforces a core program of both "stemness" and sustained tissue residency by mediating chromatin remodeling and concurrent transcriptional changes. This approach leads to a practical and clinically actionable in vitro production method for engineering peripheral blood T cells into a large number of "stem-like" CAR-TRM cells resistant to tumor-associated dysfunction, possessing an enhanced ability to accumulate in situ and rapidly eliminate cancer cells for more effective immunotherapy.
Assuntos
Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Neoplasias/terapia , Citocinas/metabolismo , ImunoterapiaRESUMO
The metabolic milieu of solid tumors provides a barrier to chimeric antigen receptor (CAR) T-cell therapies. Excessive lactate or hypoxia suppresses T-cell growth, through mechanisms including NADH buildup and the depletion of oxidized metabolites. NADH is converted into NAD+ by the enzyme Lactobacillus brevis NADH Oxidase (LbNOX), which mimics the oxidative function of the electron transport chain without generating ATP. Here we determine if LbNOX promotes human CAR T-cell metabolic activity and antitumor efficacy. CAR T-cells expressing LbNOX have enhanced oxygen as well as lactate consumption and increased pyruvate production. LbNOX renders CAR T-cells resilient to lactate dehydrogenase inhibition. But in vivo in a model of mesothelioma, CAR T-cell's expressing LbNOX showed no increased antitumor efficacy over control CAR T-cells. We hypothesize that T cells in hostile environments face dual metabolic stressors of excessive NADH and insufficient ATP production. Accordingly, futile T-cell NADH oxidation by LbNOX is insufficient to promote tumor clearance.
Assuntos
Trifosfato de Adenosina/metabolismo , Complexos Multienzimáticos/metabolismo , NADH NADPH Oxirredutases/metabolismo , Receptores de Antígenos de Linfócitos T/metabolismo , Adulto , Animais , Feminino , Humanos , Levilactobacillus brevis/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , NAD/metabolismo , Oxirredução , Linfócitos T/metabolismoRESUMO
Immune checkpoints including PD-1 and CTLA-4 help to regulate the intensity and timeframe of the immune response. Since they become upregulated in cancer and prevent sufficient antitumor immunity, monoclonal antibodies against these checkpoints have shown clinical promise for a range of cancers. Multimodal treatment plans combining immune checkpoint inhibitors with other therapies, including photodynamic therapy (PDT), may help to expand treatment efficacy and minimize side effects. PDT's cytotoxic effects are spatially limited by the light activation process, constraining PDT direct effects to the treatment field. The production of damage-associated molecular patterns and tumor-associated antigens from PDT can encourage accumulation and maturation of antigen-presenting cells and reprogram the tumor microenvironment to be more susceptible to therapies targeting immune checkpoints.
Assuntos
Antineoplásicos/uso terapêutico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias/tratamento farmacológico , Fotoquimioterapia , Antineoplásicos/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno CTLA-4/antagonistas & inibidores , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Neoplasias/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Airway complications affect roughly 15-20% of lung transplant patients. Airway stents are an attractive therapeutic option; however, no experimental or controlled observational data exists to draw firm conclusions regarding airway stent efficacy and safety in this population. METHODS: We performed a retrospective cohort study of patients who underwent airway stent placement for post-transplant anastomotic airway complications. The primary outcomes were improvements in FEV1 and reduction in bronchoscopies post-stent. RESULTS: We identified 36 patients who underwent airway stenting between October 2012 and October 2017. A total of 47 airways underwent stent placement. Improvement in FEV1 after stent placement was only observed in patients who ultimately were able to undergo stent removal. Patients who expired prior to stent removal had no immediate FEV1 improvement after stent placement. Among subjects who underwent stent removal, there was a statistically significant reduction in number of bronchoscopies per month after stent removal compared to pre-stent placement. Male gender was the only predictor of FEV1 improvement after stent placement while male gender and dehiscence prior to stent placement predicted increased number of bronchoscopies after stent placement. Mucous plugging and granulation tissue formation were the most common stent related complications. CONCLUSIONS: Only select patients benefit from stent placement for airways stenosis after lung transplant. Complications related to stent placement are common. Patients with airway complications treated with airway stents undergo a high volume of repeat procedures.
RESUMO
Immune cell function is influenced by metabolic conditions. Low-glucose, high-lactate environments, such as the placenta, gastrointestinal tract, and the tumor microenvironment, are immunosuppressive, especially for glycolysis-dependent effector T cells. We report that nicotinamide adenine dinucleotide (NAD+), which is reduced to NADH by lactate dehydrogenase in lactate-rich conditions, is a key point of metabolic control in T cells. Reduced NADH is not available for NAD+-dependent enzymatic reactions involving glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and 3-phosphoglycerate dehydrogenase (PGDH). We show that increased lactate leads to a block at GAPDH and PGDH, leading to the depletion of post-GAPDH glycolytic intermediates, as well as the 3-phosphoglycerate derivative serine that is known to be important for T cell proliferation. Supplementing serine rescues the ability of T cells to proliferate in the presence of lactate-induced reductive stress. Directly targeting the redox state may be a useful approach for developing novel immunotherapies in cancer and therapeutic immunosuppression.
Assuntos
Ácido Láctico/metabolismo , NAD/metabolismo , Proliferação de Células , Humanos , OxirreduçãoRESUMO
Given the growing interest and promising preliminary results of immunotherapy in malignant pleural mesothelioma (MPM), it has become important to more fully understand the immune landscape in this tumor. This may be especially relevant in deciding who might benefit most from checkpoint blockade or agonist antibody therapy. Since the phenotype of tumor infiltrating lymphocytes (TILs) in MPM has not been fully described and their function has not been carefully assessed, we collected fresh tumor and blood from 22 patients undergoing surgical resection and analysed single cell suspensions by flow cytometry. The functionality of TILs was assessed by measurement of cytokine expression (IFN-γ) following overnight stimulation ex vivo. Results showed low numbers of CD8+ TILs whose function was either moderately or severely suppressed. The degree of TIL hypofunction did not correlate with the presence of co-existing macrophages or neutrophils, nor with expression of the inhibitory receptors PD-1, CD39 and CTLA-4. Hypofunction was associated with higher numbers of CD4 regulatory T cells (Tregs) and with expression of the inhibitory receptor TIGIT. On the other hand, presence of tissue-resident memory (Trm) cells and expression of TIM-3 on CD8+ cells were positively associated with cytokine production. However, Trm function was partially suppressed when the transcription factor Eomesodermin (Eomes) was co-expressed. Understanding the function of TILs in malignant mesothelioma may have clinical implications for immunotherapy, especially in choosing the best immunotherapy targets. Our data suggests that Treg cell blocking agents or TIGIT inhibitor antibodies might be especially valuable in these patients.
RESUMO
Cancer progression is marked by dysfunctional tumor-infiltrating lymphocytes (TIL) with high inhibitory receptor (IR) expression. Because IR blockade has led to clinical responses in some patients with non-small cell lung cancer (NSCLC), we investigated how IRs influenced CD8+ TIL function from freshly digested early-stage NSCLC tissues using a killing assay and intracellular cytokine staining after in vitro T-cell restimulation. Early-stage lung cancer TIL function was heterogeneous with only about one third of patients showing decrements in cytokine production and lytic function. TIL hypofunction did not correlate with clinical factors, coexisting immune cells (macrophages, neutrophils, or CD4+ T regulatory cells), nor with PD-1, TIGIT, TIM-3, CD39, or CTLA-4 expression. Instead, we found that the presence of the integrin αeß7 (CD103), characteristic of tissue-resident memory cells (TRM), was positively associated with cytokine production, whereas expression of the transcription factor Eomesodermin (Eomes) was negatively associated with TIL function. These data suggest that the functionality of CD8+ TILs from early-stage NSCLCs may be influenced by competition between an antitumor CD103+ TRM program and an exhaustion program marked by Eomes expression. Understanding the mechanisms of T-cell function in the progression of lung cancer may have clinical implications for immunotherapy.
Assuntos
Carcinoma Pulmonar de Células não Pequenas/imunologia , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Idoso , Idoso de 80 Anos ou mais , Variação Biológica da População , Biomarcadores Tumorais , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma Pulmonar de Células não Pequenas/patologia , Causas de Morte , Feminino , Expressão Gênica , Humanos , Memória Imunológica , Imunofenotipagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Microambiente Tumoral/imunologiaRESUMO
Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs). The TAMs coexpressed M1/M2 markers, as well as T cell coinhibitory and costimulatory receptors. Functionally, TAMs did not primarily suppress tumor-specific effector T cell responses, whereas tumor monocytes tended to be more T cell inhibitory. TAMs expressing relevant MHC class I/tumor peptide complexes were able to activate cognate effector T cells. Mechanistically, programmed death-ligand 1 (PD-L1) expressed on bystander TAMs, as opposed to PD-L1 expressed on tumor cells, did not inhibit interactions between tumor-specific T cells and tumor targets. TAM-derived PD-L1 exerted a regulatory role only during the interaction of TAMs presenting relevant peptides with cognate effector T cells and thus may limit excessive activation of T cells and protect TAMs from killing by these T cells. These results suggest that the function of TAMs as primarily immunosuppressive cells might not fully apply to early-stage human lung cancer and might explain why some patients with strong PD-L1 positivity fail to respond to PD-L1 therapy.
Assuntos
Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Macrófagos/patologia , Monócitos/patologia , Linfócitos T/imunologia , Células A549 , Antígenos de Neoplasias/metabolismo , Biomarcadores Tumorais/metabolismo , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Comunicação Celular , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Receptores de Lipopolissacarídeos/metabolismo , Proteínas de Neoplasias/metabolismo , Estadiamento de Neoplasias , Peptídeos/metabolismo , Fenótipo , Transdução de SinaisRESUMO
T cell trafficking into tumors depends on a "match" between chemokine receptors on effector cells (e.g., CXCR3 and CCR5) and tumor-secreted chemokines. There is often a chemokine/chemokine receptor "mismatch", with tumors producing minute amounts of chemokines, resulting in inefficient targeting of effectors to tumors. We aimed to alter tumors to produce higher levels of CXCL11, a CXCR3 ligand, to attract more effector cells following immunotherapy. Mice bearing established subcutaneous tumors were studied. In our first approach, we used modified chimeric antigen receptor (CAR)-transduced human T cells to deliver CXCL11 (CAR/CXCL11) into tumors. In our second approach, we intravenously (iv) administered a modified oncolytic vaccinia virus (VV) engineered to produce CXCL11 (VV.CXCL11). The effect of these treatments on T cell trafficking into the tumors and anti-tumor efficacy after subsequent CAR T cell injections or anti-tumor vaccines was determined. CAR/CXCL11 and VV.CXCL11 significantly increased CXCL11 protein levels within tumors. For CAR/CXCL11, injection of a subsequent dose of CAR T cells did not result in increased intra-tumoral trafficking, and appeared to decrease the function of the injected CAR T cells. In contrast, VV.CXCL11 increased the number of total and antigen-specific T cells within tumors after CAR T cell injection or vaccination and significantly enhanced anti-tumor efficacy. Both approaches were successful in increasing CXCL11 levels within the tumors; however, only the vaccinia approach was successful in recruiting T cells and augmenting anti-tumor efficacy. VV.CXCL11 should be considered as a potential approach to augment adoptive T cell transfer or vaccine immunotherapy.
RESUMO
There has been dramatic success in treating patients with adoptive transfer of autologous T cells genetically modified to express a chimeric antigen receptor redirecting them to the antigen CD19. Despite this success, the application of chimeric antigen receptor T-cell therapy in solid malignancies has encountered many challenges that need to be overcome if similar success across other cancers is to become a reality. These challenges can be classified into 6 categories: the heterogeneity of tumor cell clones and tumor-associated antigen expression; poor T-cell trafficking into the tumor site; poor T-cell survival and persistence; the presence of suppressive immune cells; the secretion of suppressive soluble factors in the tumor microenvironment; and the upregulation of T-cell intrinsic inhibitory pathways. We outline specific representative hurdles in each of these categories and summarize the progress made in understanding them and developing strategies to overcome them.
Assuntos
Imunoterapia Adotiva/métodos , Neoplasias/terapia , Receptores de Antígenos/metabolismo , Linfócitos T/fisiologia , Regulação Neoplásica da Expressão Gênica , Variação Genética , Humanos , Receptores de Antígenos/genéticaRESUMO
Despite recent advances with targeted kinase inhibitors and better-tolerated chemotherapy, the treatment of metastatic non-small-cell lung cancer remains suboptimal. One recent advance that holds great promise is immunotherapy-an approach that enhances a patient's immune system to better recognize and react to abnormal cells. The most successful immunotherapeutic strategy to date uses antibodies to block inhibitory receptors (also called "checkpoints") that are up-regulated on the T cells that infiltrate the tumor. Two examples of such molecules are programmed cell death-1 (PD1) and cytotoxic T lymphocyte-associated protein-4. With more than a dozen clinical trials in non-small-cell lung cancer completed, checkpoint blockade targeting PD1 has demonstrated durable responses and superior survival compared with traditional chemotherapy agents when used as first-line therapy in individuals with more than 50% PD1 ligand (PDL1) expression by immunohistochemical staining and as second-line therapy independent of PDL1 status. Antibodies to PDL1 have shown similar activity. Combinations of anti-PD1 and anti-PDL1 with anti-cytotoxic T lymphocyte-associated protein-4 and chemotherapy are being actively tested. These agents have generally tolerable safety profiles; pneumonitis, although rare, remains the most feared adverse effect. PDL1 expression on tumors has been identified as a biomarker predictive of response. Although PDL1 expression has traditionally been measured on resected tumor specimens, the pulmonologist has a growing role in obtaining samples for testing via minimally invasive means.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais Humanizados , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/imunologia , Biomarcadores Tumorais/metabolismo , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Humanos , Imunoterapia , Neoplasias Pulmonares/imunologia , Receptor de Morte Celular Programada 1/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Linfócitos T/imunologia , Tomografia Computadorizada por Raios X , Microambiente Tumoral/efeitos dos fármacosRESUMO
Cancer immunotherapy has now become a recognized approach to treating cancers. In addition to checkpoint blockade, adoptive T cell transfer (ACT) using chimeric antigen receptors (CARs) has shown impressive clinical outcomes in leukemias and is now being explored in solid tumors. CARs are engineered receptors, stably or transiently transduced into T cells, that aim to enhance T cell effector function by recognizing and binding to a specific tumor-associated antigen. In this review, we provide a summary of CAR T cell preclinical studies and clinical trials for malignant pleural mesothelioma (MPM), a rare, locally invasive pleural cancer with poor prognosis. We list other attractive potential targets for CAR T cell therapy for MPM, and discuss augmentation strategies of CAR T cell therapy with other forms of immunotherapy in this disease.