The expression of transgenic TCRs or CARs in T lymphocytes confers potent cytotoxic activity and potential long-term persistence to these cells. However, other functional T-cell properties may need to be addressed to maximize their antitumor effects. Table 1 and Fig. 1 summarize some of the T-cell modifications that may optimize the antitumor activity of T lymphocytes. For example, CD19-specific CAR-T cells may be more effective for the treatment of ALL than of lymphoma in part because they more efficiently eliminate tumor cells from the circulation and bone marrow than the lymph nodes. Many lymphomas are characterized by a particular chemokine milieu to which engineered T cells can be adapted. For example, Hodgkin lymphomas may produce high levels of TARC, and T cells coexpressing a CAR specific for the Hodgkin disease–associated CD30 antigen and a transgenic chemokine receptor CCR4 have significantly enhanced traffic king to the tumor and consequently better antitumor activity in animal models. Even when tumor-specific T cells efficiently reach the tumor environment, other tumor-associated factors may hamper T-cell survival and function. For example, many tumors, including hematologic malignancies, and their tumor-associated stroma produce TGF-β, which favors the development of immune tolerance and T-cell anergy, inducing T effector cell growth arrest with induction of regulatory T cells. Transfection of a dominant negative form of TGF-β RII (dnTGF-β RII) confers resistance to the antiproliferative effects of TGF-β and improves the persistence of T cells and antitumor effects in preclinical models. Such an approach has been studied in patients with refractory EBV-associated Hodgkin lymphoma, with the infusion of TGF-β-resistant tumor-specific T cells leading to clinical responses in four out of seven evaluable patients, two of which achieved durable complete responses lasting over 4 years.

Table1. Causes of Immunosuppression in Cancer Patients

Fig1. GENETIC MODIFICATIONS OF T LYMPHOCYTES FOR ADOPTIVE T-CELL THERAPY.

Achievement of sustained clinical responses upon T-cell transfer is strongly dependent on in vivo T-cell expansion and persistence, which in turn requires the infused T cells to contain a population with a stemness/memory signature and the availability of cytokines that sustain T-cell replication and survival. We do not yet know the optimal means by which stem/memory T cells can be preserved before adoptive transfer. Nonetheless it is clear that infusion of tumor-specific T cells in a lymphodepleted host benefits T-cell expansion, likely because the infused T cells can exploit the favor able homeostatic cytokine milieu (including production of IL-7 and IL-15) and the transient depletion of regulatory T cells. Exogenous cytokines such as recombinant IL-2 can also be infused but may cause significant toxicity and concomitant expansion of regulatory T cells. Recombinant IL-15 infusions were anticipated to be more effective and better tolerated than IL-2, but toxicity remains problematic.27 Thus investigators have developed T-cell engineering strategies that make tumor-directed T cells which produce their own cytokines or express receptors for specific cytokines.10 While these approaches are effective in preclinical models, and multiple clinical trials are ongoing, we do not yet know if they can replace or augment the use of lymphodepleting agents before adoptive transfer.

The molecular pathways responsible for the regulation and con traction of the T-cell immune response (immune check-points) have become a major focus of effective immunotherapies, and monoclonal antibodies that interrupt pathways such as the CD28/CTLA-4 and the PD-1/PD-L1 axes have emerged as potent new agents for the treatment of cancer, inducing sustained clinical responses in tumors likely mediated by the functional release of suppressed tumor-specific T cells recognizing neoantigens. Many investigators therefore believe that the adoptive transfer of tumor-specific T cells and potentially CAR-T cells generated ex vivo will synergize with infusion of check point antibodies, and this is an active area of clinical research.

Despite the remarkable successes of the CAR-T cell therapies out lined above and in Table 2, most patients will ultimately relapse. In addition to the factors discussed above, loss of expression of the target antigen is another important mechanism by which tumors may develop resistance to targeting by transgenic TCR- or CAR expressing T cells. Such therapies exert significant selection pressure, and patients with B-ALL who have relapsed following CD19-directed CAR–T-cell therapy have been found to harbor a variety of potential genetic alterations, including frameshift mutations leading to a loss of the CD19 transmembrane domain, expression of splice variants with a loss of the exon encoding the epitope targeted by the CAR scFv, or splice variants preventing expression of the anchoring transmembrane domain.18 In AML and MM especially, there is also concern for so called leukemic and myeloma “stem cell” populations, respectively. These “stem cell” populations are hypothesized to have increased resistance to traditional chemotherapy agents, but may also lack expression of cell surface proteins targeted by existing CAR-T therapies. To overcome these potential limitations, there has thus been significant interest in bispecific CAR-T cells and multiple technical variations of this concept are under investigation. There are currently multiple clinical trials underway evaluating bispecific CAR-T cells, primarily for B-cell malignancies (e.g., CD19/CD20 and CD19/CD22).

Table2. Selected Clinical Trials Using Chimeric Antigen Receptors−Modified and T-Cell Receptor−Modified T Cells

اخر الاخبار

اخبار العتبة العباسية المقدسة

قسم الشؤون الفكرية يصدر كتابًا توثيقيًّا عن جرائم الإرهاب بحق زائري الأربعين في العراق

في مقابلة خاصة مع المشرف على قسم الشؤون الطبية: مركز السيد جعفر الحلي يعزز الاستجابة الطبية الطارئة ولا سيّما في الزيارات المليونية

لمنتسبي العتبة العباسية المقدسة.. قسم الشؤون الدينية يجري الاختبارات العملية للمشاركين في الدورة التطويرية الثانية

المجمع العلمي يقيم الدورة الــ 20 في تعليم أحكام التلاوة لطلبة العلوم الدينية

المزيد

الآخبار الصحية

العلاج بالماء البارد.. باحثون يكشفون فوائده الصحية

من دون صالة رياضية.. عادة بسيطة لتحسين الصحة وخسارة الوزن

لصحة القلب وتفادي السرطان.. استهلك هذا النوع من الطعام

دراسة تحذر من خطر شرب القهوة في أكواب البلاستيك

المزيد

الآخبار التكنلوجية

إنجاز طبي تاريخي.. جراحة قلب بلا شق في الصدر

اليابان.. مراحيض توفر فحص للحالة الصحية عبر "تحليل البراز" !

اختراق واسع لمنصة "إنستغرام".. ونشر بيانات على "الدارك ويب"

علماء يحذرون: هكذا سيفنى كوكب الأرض

المزيد

مواضيع ذات صلة

T Lymphocytes, Transfer of Safety Genes, and Strategies to Improve Tumor Cell Specificity

Allogeneic Banked Cells

Clinical Results of Chimeric Antigen Receptor T Cells in Hematologic Malignancies

Types of Cellular Immunotherapy

Adoptive Immunotherapy of Cancer

Therapeutic Manipulation of T-Cell-Mediated Immunity

T-Cell Exhaustion: Impaired Response after Chronic Antigen Exposure

T-Cell Memory

Regulatory T Cells

T-Cell Function

The T-Cell Receptor Complex

Antigen Presentation: Creating the Ligand for the T-Cell Receptor