A major problem of any successful cell therapy is that adverse events produced by the infused cells may persist and worsen if the cells survive and proliferate. A classic example is the GVHD that occurs when allogeneic donor T cells are transferred with the hematopoietic graft. It is also clear, however, that even nonalloreactive T cells may cause serious and even lethal toxicities, particularly if they are genetically modified to target highly expressed self-antigens present both on tumors and normal tissues. Examples include CRS and ICANS as discussed above with CAR-T-cell therapy, as well as potential on-tumor, off-target toxicities. In addition, efforts to enhance the survival and expansion of T cells could lead to uncontrolled expansion of the manipulated T cells, an event that might even occur as a result of retroviral genotoxicity alone, although this has been observed primarily in clinical studies of hematopoietic stem cells transduced by murine oncoretroviral vectors and has not emerged as a significant limitation of CAR-T-cell therapy. For all these reasons, there has been increasing interest in the incorporation of safety switches or suicide genes in any T cell that is adoptively transferred to humans.

Safety or suicide genes have been best studied in the recipients of DLI in patients with hematologic malignancies relapsed after allogeneic HSCT to prevent the occurrence of GVHD. Adequate doses of donor T cells can only be safely given if there is some means by which unwanted alloreactivity can be abrogated in vivo. Efforts have been made to achieve this aim by genetically modifying T cells through the introduction of suicide genes.

Herpes simplex thymidine kinase (HSVtk) was the first such transgene to be studied in the context of adoptive cellular therapy. HSVtk phosphorylates specific nucleoside analogues, including ganciclovir, to nucleoside monophosphates. These compounds block effective DNA synthesis and kill dividing cells. In several clinical trials, this gene has been transferred to donor T lymphocytes, which have then been given to the allogeneic stem cell transplant recipient to prevent or treat relapse. While HSVtk gene-modified T cells have been shown to persist in the circulation in most patients, and to be removed after the administration of ganciclovir, often with an improvement in GVHD, several problems have limited the use of this approach. HSVtk is a viral protein and in some patients, a cell-mediated immune response against HSVtk is detected, causing undesired premature elimination of transgenic cells. Other drawbacks of HSVtk include the unintended elimination of gene-modified cells when ganciclovir is used for treatment of CMV reactivation, ganciclovir resistance that may occur from truncated HSVtk generated from cryptic splice donor and acceptor sites, and slow elimination of transgenic cells as HSVtk requires DNA synthesis to be active; such delayed activity may be undesirable if T cells are acutely toxic. Alternative strategies have included the genetic modification of T cells to express CD20 or truncated epidermal growth factor receptor (EGFRt), allowing the use of rituximab or cetuximab, respectively, to eliminate the modified T cells via complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC). While these approaches are being incorporated into multiple ongoing clinical trials, there are significant potential limitations, including the biodistribution of the infused monoclonal antibody and on-target toxicity from the antibody.

Investigators attempted to overcome some of these limitations by developing new suicide genes based on human molecules that are potentially less immunogenic and which overcome the limitations related to antibody bioavailability. In particular, suicide genes have been generated based on chimeric molecules derived from human proteins involved in the apoptotic pathway, which have been modified to be activated by a small molecule (inducible Fas and inducible Caspase9 [iC9]). Two clinical studies have used the iC9 gene, which consists of the human FK506-binding protein sequence with an F36V mutation, connected to human caspase-9 deleted for its endogenous activation and caspase-activating recruitment domain. FKBP12-F36V binds with high affinity an otherwise bioinert small molecule dimerizing agent (AP1903). In the presence of the drug, the iCasp9 promolecule dimerizes and activates the intrinsic apoptotic pathway leading to cell death. The study infused donor-derived iCas pase9-T cells after haploidentical stem cell transplant and if patients developed GVHD, administered a single dose of the dimerizing drug. There was rapid destruction of greater than 95% of the cells with prompt resolution of GVHD and faster immune reconstitution that allowed robust protection against opportunistic infection. This system has been incorporated into CAR-T-cell constructs being evaluated in multiple ongoing clinical trials, including an ongoing trial of CD19-specific CAR-T cells for relapsed/refractory ALL.

The safety genes discussed above will likely become increasingly important tools to minimize potentially severe toxicities such as CRS and ICANS. However, these strategies can only be utilized once such toxicities have already developed. A preventative strategy will depend on an improved understanding of the mechanisms underlying these syndromes.

Although less of a concern for B-cell malignancies given the relative tolerability of the off-tumor, on-target toxicity directed at normal B cells that accompanies CD19-directed cellular therapies, potential on-target toxicities remain a significant barrier toward the wider applicability of TCR- and CAR-engineered T-cell therapies. For most other malignancies, the applicability of CAR-T-cell therapies has been limited by the difficulty in identifying a single target antigen that can be safely targeted without the risk of unacceptable on-target toxicities. There has thus been significant pre-clinical work toward the development of strategies that could improve the specificity of CAR-T cells for tumor cells. Dual antigen recognition strategies have been hypothesized that would allow better discrimination between tumor cells and normal tissue. One compelling pre-clinical example involves a combinatorially activated T-cell circuit, referred to as a “two antigen AND-gate circuit,” in which activation of a synthetic Notch receptor for one antigen induces expression of a CAR targeted toward a second antigen. At this point, however, the clinical feasibility of such strategies has yet to be demonstrated.

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

Optimizing T-Cell Trafficking and Overcoming Tumor Immune Evasion

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