Molecular immunology lessons from therapeutic T‐cell receptor gene transfer

The T‐cell receptor (TCR) is critical for T‐cell lineage selection, antigen specificity, effector function and survival. Recently, TCR gene transfer has been developed as a reliable method to generate ex vivo large numbers of T cells of a given antigen‐specificity and functional avidity. Such approaches have major applications for the adoptive cellular therapy of viral infectious diseases, virus‐associated malignancies and cancer. TCR gene transfer utilizes retroviral or lentiviral constructs containing the gene sequences of the TCR‐α and TCR‐β chains, which have been cloned from a clonal T‐cell population of the desired antigen specificity. The TCR‐encoding vector is then used to infect (transduce) primary T cells in vitro. To generate a transduced T cell with the desired functional specificity, the introduced TCR‐α and TCR‐β chains must form a heterodimer and associate with the CD3 complex in order to be stably expressed at the T‐cell surface. In order to optimize the function of TCR‐transduced T cells, researchers in the field of TCR gene transfer have exploited many aspects of basic research in T‐cell immunology relating to TCR structure, TCR–CD3 assembly, cell‐surface TCR expression, TCR‐peptide/major histocompatibility complex (MHC) affinity and TCR signalling. However, improving the introduction of exogenous TCRs into naturally occurring T cells has provided further insights into basic T‐cell immunology. The aim of this review was to discuss the molecular immunology lessons learnt through therapeutic TCR transfer.     

Genetic engineering of T cell specificity for immunotherapy of cancer

The ultimate goal of immunotherapy of cancer is to make use of the immune system of patients to eliminate malignant cells. Research has mainly focused on the generation of effective antigen specific T-cell responses because of the general belief that T-cell immunity is essential in controlling tumor growth and protection against viral infections. However, the isolation of antigen specific T cells for therapeutic application is a laborious task and it is often impossible to derive autologous tumor specific T cells to be used for adoptive immunotherapy. Therefore, strategies were developed to genetically transfer tumor specific immune receptors into patients T cells. To this end, chimeric receptors were constructed that comprise antibody fragments specific for tumor associated antigens, linked to genes encoding signaling domains of the T-cell receptor (TCR) or Fc receptor. T cells expressing such chimeric antibody receptors recapitulate the immune specific responses mediated by the introduced receptor. Recently, we introduced chimeric TCR genes into primary human T lymphocytes and demonstrated that these T cell transductants acquired the exquisite major histocompatibility complex (MHC) restricted tumor specificity dictated by the introduced TCR. Importantly, the introduction of chimeric TCR bypasses problems associated with the introduction of nonmodified TCR genes, such as pairing of introduced TCR chains with endogenous TCR chains and unstable TCRalpha expression. A novel strategy which is completely independent of available tumor specific T-cell clones for cloning of the TCR genes was recently used to transfer MHC restricted tumor specificity to T cells. Human "TCR-like" Fab fragments obtained by in vitro selection of Fab phages on soluble peptide/MHC complexes were functionally expressed on human T lymphocytes, resulting in MHC restricted, tumor specific lysis and cytokine production. In addition, affinity maturation of the antibody fragment on Fab phages allows improvement of the tumor cell killing capacity of chimeric Fab receptor engrafted T cells. Developments in retroviral transfer technology now enables the generation of large numbers of antigen specific T cells that can be used for adoptive transfer to cancer patients. In this article we summarize the developments in adoptive T cell immunogenetic therapy and discuss the limitations and perspectives to improve this technology toward clinical application.     

Avidity optimization of a MAGE-A1-specific TCR with somatic hypermutation

A T-cell receptor (TCR) with optimal avidity to a tumor antigen can be used to redirect T cells to eradicate cancer cells via adoptive cell transfer. Cancer testis antigens (CTAs) are attractive targets because they are expressed in the testis, which is immune-privileged, and in the tumor. However, CTAs are self-antigens and natural TCRs to CTAs have low affinity/avidity due to central tolerance. We previously described a method of directed evolution of TCR avidity using somatic hypermutation. In this study, we made several improvements to this method and enhanced the avidity of the hT27 TCR, which is specific for the cancer testis antigen HLA-A2-MAGE-A1_278-286. We identified eight point mutations with varying degrees of improved avidity. Human T cells transduced with TCRs containing these mutations displayed enhanced tetramer binding, IFN-γ and IL2 production, and cytotoxicity. Most of the mutations have retained specificity, except for one mutant with extremely high avidity. We demonstrate that somatic hypermutation is capable of optimizing avidity of clinically relevant TCRs for immunotherapy.     

Engineering antigen‐specific NK cell lines against the melanoma‐associated antigen tyrosinase via TCR gene transfer

Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic T‐lymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTL‐TCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with off‐target specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/β chains, along with CD3 subunits, enables the functional expression of an antigen‐specific TCR complex on NK cell lines NK‐92 and YTS, demonstrated by using a TCR against the HLA‐A2‐restricted tyrosinase‐derived melanoma epitope, Tyr_368‐377. Most importantly, the introduction of a TCR complex to NK cell lines enables MHC‐restricted, antigen‐specific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of “mispairing” in TCR gene therapy.     

gammadelta T-cell clones from intestinal intraepithelial lymphocytes inhibit development of CTL responses ex vivo

Oral administration of antigen induces a state of tolerance that is associated with activation of CD8⁺ T cells that can transfer unresponsiveness to naïve syngeneic hosts. These T cells are not lytic, but they inhibit development of antibody, CD4⁺ T helper cell, and CD8⁺ cytotoxic T lymphocyte (CTL) responses upon adoptive transfer into naïve, syngeneic mice. In addition, we have shown that depletion of γδ T cells by injection of the anti‐δ chain antibody (GL3) down modulates the expression of γδ T‐cell receptor (TCR) and inhibits the induction of oral tolerance to ovalbumin. Oral administration of antigen also fails to induce tolerance in TCR δ‐chain knockout mice suggesting that γδ T cells play a critical, active role in tolerance induced by orally administered antigen. To further study the contribution of γδ T cells to tolerance, murine γδ T cells were isolated from intraepithelial lymphocytes (IEL) of the small intestine by stimulation with splenic filler cells, concanavalin A and growth factors. γδ IEL lines demonstrated lytic activity in a redirected lysis assay. γδ T‐cell clones express different γδ TCR genes and secrete large amounts of interleukin (IL)‐10, but little or no IL‐2, IL‐4, or interferon‐γ. γδ IEL clones expressed transforming growth factor‐β1 and macrophage migration inhibitory factor, as well as IL‐10, mRNA. Moreover, γδ T‐cell clones potently inhibited the generation of CTL responses by secreted molecules rather than by direct cell‐to‐cell contact.     

Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor

CD8(+) T cell tolerance, although essential for preventing autoimmunity, poses substantial obstacles to eliciting immune responses to tumor antigens, which are generally overexpressed normal proteins. Development of effective strategies to overcome tolerance for clinical applications would benefit from elucidation of the immunologic mechanism(s) regulating T cell tolerance to self. To examine how tolerance is maintained in vivo, we engineered dual-T cell receptor (TCR) transgenic mice in which CD8(+) T cells recognize two distinct antigens: a foreign viral-protein and a tolerizing self-tumor protein. Encounter with peripheral self-antigen rendered dual-TCR T cells tolerant to self, but these cells responded normally through the virus-specific TCR. Moreover, proliferation induced by virus rescued function of tolerized self-tumor-reactive TCR, restoring anti-tumor activity. These studies demonstrate that peripheral CD8(+) T cell tolerance to self-proteins can be regulated at the level of the self-reactive TCR complex rather than by central cellular inactivation and suggest an alternate strategy to enhance adoptive T cell immunotherapy.     

Designer T cells by T cell receptor replacement

T cell receptor (TCR) gene transfer is a convenient method to produce antigen-specific T cells for adoptive therapy. However, the expression of two TCR in T cells could impair their function or cause unwanted effects by mixed TCR heterodimers. With five different TCR and four different T cells, either mouse or human, we show that some TCR are strong--in terms of cell surface expression--and replace weak TCR on the cell surface, resulting in exchange of antigen specificity. Two strong TCR are co-expressed. A mouse TCR replaces human TCR on human T cells. Even though it is still poorly understood why some TCRalpha/beta combinations are preferentially expressed on T cells, our data suggest that, in the future, designer T cells with exclusive tumor reactivity can be generated by T cell engineering.     

Different affinity windows for virus and cancer‐specific T‐cell receptors: Implications for therapeutic strategies

T‐cell destiny during thymic selection depends on the affinity of the TCR for autologous peptide ligands presented in the context of MHC molecules. This is a delicately balanced process; robust binding leads to negative selection, yet some affinity for the antigen complex is required for positive selection. All TCRs of the resulting repertoire thus have some intrinsic affinity for an MHC type presenting an assortment of peptides. Generally, TCR affinities of peripheral T cells will be low toward self‐derived peptides, as these would have been presented during thymic selection, whereas, by serendipity, binding to pathogen‐derived peptides that are encountered de novo could be stronger. A crucial question in assessing immunotherapeutic strategies for cancer is whether natural TCR repertoires have the capacity for efficiently recognizing tumor‐associated peptide antigens. Here, we report a comprehensive comparison of TCR affinities to a range of HLA‐A2 presented antigens. TCRs that bind viral antigens fall within a strikingly higher affinity range than those that bind cancer‐related antigens. This difference may be one of the key explanations for tumor immune escape and for the deficiencies of T‐cell vaccines against cancer.     

Plasmacytoid dendritic cells and type 1 interferon promote peripheral expansion of forkhead box protein 3+ regulatory T cells specific for the ubiquitous RNA‐binding nuclear antigen La/Sjögren's syndrome (SS)‐B

RNA‐binding nuclear antigens are a major class of self‐antigen to which immune tolerance is lost in rheumatic diseases. Serological tolerance to one such antigen, La/Sjögren's syndrome (SS)‐B (La), is controlled by CD4⁺ T cells. This study investigated peripheral tolerance to human La (hLa) by tracking the fate of hLa‐specific CD4⁺ T cells expressing the transgenic (Tg) 3B5.8 T cell receptor (TCR) after adoptive transfer into lymphocyte‐replete recipient mice expressing hLa as a neo‐self‐antigen. After initial antigen‐specific cell division, hLa‐specific donor CD4⁺ T cells expressed forkhead box protein 3 (FoxP3). Donor cells retrieved from hLa Tg recipients displayed impaired proliferation and secreted interleukin (IL)?10 in vitro in response to antigenic stimulation. Transfer of highly purified FoxP3‐negative donor cells demonstrated that accumulation of hLa‐specific regulatory T cells (T_reg) was due primarily to expansion of small numbers of donor T_reg. Depletion of recipient plasmacytoid dendritic cells (pDC), but not B cells, severely hampered the accumulation of FoxP3⁺ donor T_reg in hLa Tg recipients. Recipient pDC expressed tolerogenic markers and higher levels of co‐stimulatory and co‐inhibitory molecules than B cells. Adoptive transfer of hLa peptide‐loaded pDC into mice lacking expression of hLa recapitulated the accumulation of hLa‐specific T_reg. Blockade of the type 1 interferon (IFN) receptor in hLa Tg recipients of hLa‐specific T cells impaired FoxP3⁺ donor T cell accumulation. Therefore, peripheral expansion of T_reg specific for an RNA‐binding nuclear antigen is mediated by antigen‐presenting pDC in a type 1 IFN‐dependent manner. These results reveal a regulatory function of pDC in controlling autoreactivity to RNA‐binding nuclear antigens.     

Immunomodulation in the treatment of haematological malignancies

Despite the continuous advances in immunology and cancer biology, haematological malignancies are often incurable. Conventional chemotherapy and radiation are efficacious for some lymphoma and leukaemia, however relapse and progressive disease often occurs. The evidence that the immune system can play an essential role in controlling cancer progression provide a basis for the development of active therapies, such as immunization, aimed to evoke or amplify a tumour-specific immune response. However, the inability of the patient’s own immune system to mount effective responses against tumour antigens is a major limit of vaccination approaches. The adoptive transfer of effectors of the adaptive immune system is an attractive strategy to circumvent the limitations of autologous immune responses. Donor lymphocyte infusion and the transfer of monoclonal antibodies (MoAbs) have been the first forms of adoptive therapy approved for clinical use and are still fundamental components of immunotherapy of haematological malignancies. Due to the continuous characterization of tumour-specific antigen, the development of tumour-tailored therapies that exploit the specificity of antibodies and T cell receptors (TCRs) is progressing rapidly. This review highlights the current advances in the field of adoptive immunotherapy of haematological malignancies, starting by elucidating the ongoing progress in passive transfer of MoAbs. We will also discuss recent advances in the adoptive transfer with tumour-specific high avidity T cells, which can be generated ex vivo by the transfer of gene constructs encoding single chain antibodies or TCRs, thus redirecting T cell specificity to selected tumour antigens. The ability to produce gene-modified T cells of desired specificity and defined functional activity may improve in the future T cell based immunotherapy of cancer.     

Conflicting consequences of immunity to cancer versus autoimmunity to neurons: Insights from paraneoplastic disease

Immunologists are well aware that cancer regression and increased patient survival with the use of checkpoint inhibitors, such as ipilimumab, an antibody directed against cytotoxic T‐lymphocyte–associated antigen 4, CTLA‐4 (CD152), is accompanied by concomitant autoimmunity. For over 30 years, a small group of investigators have shown that the rare paraneoplastic syndromes are caused by immunity to shared antigens found on both tumors and on components of the nervous system. In this issue of the European Journal of Immunology, Blachère et al. [Eur. J. Immunol. 2014. 44: 3240–3251] elucidate some of the molecular mechanisms underlying the tolerance to neuronal antigens which share epitopes with oncologic antigens, observed in the context of paraneoplastic syndromes in mice. The presence of the shared tumor antigen on a nonhematopoietic cell underlies the basis for a certain level of tolerance in CD4⁺ and CD8⁺ T cells, preventing these cells from attacking the brain, but allowing them to lyse the tumor upon transfer into tumor‐bearing recipient mice. Comparisons between the paraneoplastic syndromes and the new autoimmune conditions seen with antibodies to immune checkpoints at CD152 or at CD279 are likely to illuminate shared mechanisms and solutions to these vexing diseases.     

Effector-phase tolerance: another mechanism of how cancer escapes antitumor immune response

Growth of cancer in rodent models and in patients elicits immune responses directed toward various antigens expressed by the transformed cell. Clearly though, as most tumors grow, unmanipulated antitumor immune responses are incapable of eliminating cancer. Over the past approximately 15 years, antitumor immunoglobulin and T cells have been used to identify tumor antigens, which in turn, have served as the basis for therapeutic vaccine trials. However, experimental cancer vaccines, although in some patients result in elimination of large tumor burdens, have a low frequency of long-term cancer remission in most patients, ca. <5%. Therefore, as tumors express antigens that distinguish themselves from nontransformed cells in immunological terms (i.e., elicit immune responses to growth of primary tumor and can target tumor cells in vivo), and tumor vaccines prime unsuccessful antitumor immune responses in patients, it is likely that growth of cancer induces immune tolerance to tumor cells. Although there are several types of T cell tolerance, mature, antigen-specific CD8+ T cells isolated from tumors are lytic-defective, implying that the tumor microenvironment inactivates the antitumor effector phase. The nature of the functional local tolerance to antitumor immune response is the subject of this review.     

Molecular pathological approaches to human tumor immunology

Research on human tumor immunology has greatly advanced in the past two decades. Many immunogenic tumor antigens have been identified, and some of these antigens entered in clinical trials. Consequently, it has been shown that these antigens can inhibit tumor growth in patients to some extent, indicating that they act as potent immunogenic therapeutic vaccines in cancer patients with malignancies originating from various tissues. These patients had antigen‐specific cytotoxic T‐lymphocyte (CTL) responses when assessed on tetramer, enzyme‐linked immunospot (ELISPOT), T‐cell clonotype and CTL induction efficiency. Thus, it has become clear that human tumor vaccines can evoke clinical and immunological anti‐tumor responses in patients. The tumor regression effects of tumor vaccines, however, are generally low, and it is obvious that current vaccination protocols are generally too weak to provide substantial and satisfactory clinical benefits. This means that other drastic and more potent clinical and immunological protocols are required in cancer immunotherapy. To find such efficient protocols the basic immunological and biological properties of cancers must be investigated. In the present review the identification of human tumor antigens recognized on CTL and the clinical trials are introduced. Next, the most recent analysis of human cancer‐initiating cell (cancer stem cell)‐associated antigens is described. These antigens might be able to act as ‘universal, general and fundamental’ tumor antigens. Also present is the authors' recent study for increasing cross‐presentation efficiency in dendritic cells and subsequent enhancement of human leukocyte antigen (HLA)‐class I‐restricted peptide antigenicity by using HSP90 and ORP150 molecular chaperones that act as endogenous Toll‐like receptor ligands. In addition to the aforementioned manipulation of the positive loop of tumor immunity, it is necessary to regulate and intervene in the negative loop. In particular, the potential of the expression of HLA class I molecule regulation by epigenetic mechanisms will be discussed. Finally, the type of basic and clinical tumor immunology research highly required currently, and in the very near future, are described.     

Cancer immunogene therapy.

The establishment of cancer in a host involves at least two major events: the escape of tumor cells from normal growth control and their escape from immunological recognition. Because of this nature of their development, cancer cells seem to be predominatly poorly immunogenic. In contrast to the previous idea that cancer cells express no recognizable antigens, recent progress in the identification and characterization of tumor antigens, as well as the expansion of knowledge on the cellular and molecular mechanisms of antigen recognition by the immune system, have raised the possibility of using immunotherapy to treat certain tumors. Information on these mechanisms has been obtained in three crucial areas: 1) the role of cytokines in the regulation of the immune response, 2) the molecular characterization of tumor antigens in both mouse and human tumors, and 3) the molecular mechanisms of T cell activation and antigen presentation. Such information has provided new insight into tumor immunology and immunotherapy. Furthermore, recombinant DNA technology allows for modification of the genome of mammalian cells for therapeutic purposes in several diseases. Several novel strategies have been developed to derive genetically modified tumor cells and use them as cellular vaccines to induce antitumor immunity in animal tumor models. This combined modality of genetically modified tumor cells and immunotherapy has been termed immunogene therapy of tumors. Crucial to this approach has been the ability to transfer into normal or neoplastic cells genes known to increase the immunogenicity of cells, which subsequently can be used to augment immune reactions in tumor-bearing mice or cancer patients. While there has been success in inducing antitumor immunity in some tumor models, there are difficulties and limitations in the application of these gene-modified tumor cells for the treatment of preexisting tumors. In this review, recent progress in cancer immunogene therapy is discussed.     

T cell avidity and tumor recognition: implications and therapeutic strategies

In the last two decades, great advances have been made studying the immune response to human tumors. The identification of protein antigens from cancer cells and better techniques for eliciting antigen specific T cell responses in vitro and in vivo have led to improved understanding of tumor recognition by T cells. Yet, much remains to be learned about the intricate details of T cell – tumor cell interactions. Though the strength of interaction between T cell and target is thought to be a key factor influencing the T cell response, investigations of T cell avidity, T cell receptor (TCR) affinity for peptide-MHC complex, and the recognition of peptide on antigen presenting targets or tumor cells reveal complex relationships. Coincident with these investigations, therapeutic strategies have been developed to enhance tumor recognition using antigens with altered peptide structures and T cells modified by the introduction of new antigen binding receptor molecules. The profound effects of these strategies on T cell – tumor interactions and the clinical implications of these effects are of interest to both scientists and clinicians. In recent years, the focus of much of our work has been the avidity and effector characteristics of tumor reactive T cells. Here we review concepts and current results in the field, and the implications of therapeutic strategies using altered antigens and altered effector T cells.     

Gut T cell receptor‐γδ+ intraepithelial lymphocytes are activated selectively by cholera toxin to break oral tolerance in mice

The gut immune system is usually tolerant to harmless foreign antigens such as food proteins. However, tolerance breakdown may occur and lead to food allergy. To study mechanisms underlying food allergy, animal models have been developed in mice by using cholera toxin (CT) to break tolerance. In this study, we identify T cell receptor (TCR)‐γδ⁺ intraepithelial lymphocytes (IELs) as major targets of CT to break tolerance to food allergens. TCR‐γδ⁺ IEL‐enriched cell populations isolated from mice fed with CT and transferred to naive mice hamper tolerization to the food allergen β‐lactoglobulin (BLG) in recipient mice which produce anti‐BLG immunoglobulin (Ig)G1 antibodies. Furthermore, adoptive transfer of TCR‐γδ⁺ cells from CT‐fed mice triggers the production of anti‐CT IgG1 antibodies in recipient mice that were never exposed to CT, suggesting antigen‐presenting cell (APC)‐like functions of TCR‐γδ⁺ IELs. In contrast to TCR‐αβ⁺ cells, TCR‐γδ⁺ IELs bind and internalize CT both in vitro and in vivo. CT‐activated TCR‐γδ⁺ IELs express major histocompatibility complex (MHC) class II molecules, CD80 and CD86 demonstrating an APC phenotype. CT‐activated TCR‐γδ⁺ IELs migrate to the lamina propria, where they produce interleukin (IL)‐10 and IL‐17. These results provide in‐vivo evidence for a major role of TCR‐γδ⁺ IELs in the modulation of oral tolerance in the pathogenesis of food allergy.     

T-cell receptor revision: friend or foe?

T‐cell receptor (TCR) revision is a process of tolerance induction by which peripheral T cells lose surface expression of an autoreactive TCR, reinduce expression of the recombinase machinery, rearrange genes encoding extrathymically generated TCRs for antigen, and express these new receptors on the cell surface. We discuss the evidence for this controversial tolerance mechanism below. Despite the apparent heresy of post‐thymic gene rearrangement, we argue here that TCR revision follows the rules obeyed by maturing thymocytes undergoing gene recombination. Expression of the recombinase is carefully controlled both spatially and temporally, and may be initiated by loss of signals through surface TCRs. The resulting TCR repertoire is characterized by its diversity, self major histocompatibility complex restriction, self tolerance, and ability to mount productive immune responses specific for foreign antigens. Hence, TCR revision is a carefully regulated process of tolerance induction that can contribute to the protection of the individual against invading pathogens while preserving the integrity of self tissue.     

Enhanced stimulation of anti-ovarian cancer CD8(+) T cells by dendritic cells loaded with nanoparticle encapsulated tumor antigen

Citation
Hanlon DJ, Aldo PB, Devine L, Alvero AB, Engberg AK, Edelson R, Mor G. Enhanced stimulation of anti‐ovarian cancer CD8⁺ T cells by dendritic cells loaded with nanoparticle encapsulated tumor antigen. Am J Reprod Immunol 2011; 65: 597–609 Problem Dendritic cell (DC)‐based cancer therapies are favored approaches to stimulate anti‐tumor T‐cell responses. Unfortunately, tolerance to tumor antigens is difficult to overcome. Biodegradable poly(lactic‐co‐glycolic acid) (PLGA) nanoparticles (NP) are effective reagents in the delivery of drugs and tumor‐associated antigens (TAA). In this study, we assessed the capacity of a PLGA NP‐based delivery system to augment CD8 T‐cell responses to ovarian cancer TAA. Method of Study Human DC were generated from blood monocytes by conventional in vitro differentiation and loaded with either soluble tumor lysate or NP/lysate conjugates (NPL). These antigen‐loaded DC were then used to stimulate autologous CD8⁺ T cells. Cytokine production and activation markers were evaluated in the CD8⁺ T cells. Results DC loading with NPL increased cytokine production by stimulated CD8 T cells and induced T‐cell expression of cell surface co‐stimulatory molecules, typical of anti‐tumor immune responses. In contrast, delivery of naked tumor lysate antigens preferentially induced a T‐cell profile characteristic of tolerization/exhaustion. Conclusion These findings indicate that delivery of TAA in NP enables DC to efficiently activate anti‐tumor CD8⁺ T cells. PLGA NP encapsulation of tumor‐derived lysate protein antigens is an encouraging new preparative methodology for DC‐based vaccination meriting clinical testing.     

基因治疗在肿瘤过继性免疫治疗中的应用

过继性输注肿瘤浸润性淋巴细胞(TILs)能可靠地治疗转移性黑色素瘤,并使其有效率稳定在50%左右.但由于受TIL来源的限制,大多数非黑色素瘤病人无法使用过继性免疫治疗.使用抗肿瘤抗原TCR修饰的T淋巴细胞成功用于黑色素瘤病人的治疗为非黑色素瘤癌症病人的过继性免疫治疗提供了方向.本综述介绍了近几年来肿瘤特异性过继免疫治疗的进展,重点介绍基因修饰的T淋巴细胞的应用及存在的问题,并展望了发展前景.