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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 179-185

Chimeric antigen receptor T-cell therapy in hematopoietic and nonhematopoietic malignancies


Department of Medical Elementology and Toxicology, Jamia Hamdard, New Delhi, India

Date of Submission29-Apr-2020
Date of Acceptance02-May-2020
Date of Web Publication12-Sep-2020

Correspondence Address:
Mr. Faizan Ahmad
Qno B/730, H.E.C, Sector 2, Dhurwa, Ranchi, Jharkhand
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_64_20

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  Abstract 


Chimeric antigen receptor (CAR) T-cell therapy is an advanced personalized immunotherapy used in the treatment of many cancers. Basically, an immunotherapy uses the body's own immune system to detect and destroy the cancerous cells. The isolated T-cells from patients are genetically engineered to identify and target the elimination of cancer cells. Such T-cells, after genetic modification, are known as CAR-T cells. Most recently, the CAR-T cells are developed which show a remarkable ability to treat leukemia along with combinatorial treatment (e.g., Tisagenlecleucel) and lymphoma (e.g., Axicabtagene and Ciloleucel). Furthermore, these drugs have received FDA regulatory approval in the United States. Hence, more exploratory researches are the need of the hour in the CAR-T cell therapy of solid tumors to make it accessible and affordable for patients. The paper reviews various approaches and advancements of CAR-modified T-cell therapy, its persistence, and homing, along with the concept of universal CAR-T cell development. The usage of genetically engineered T-cells for treating B-cell tumor, especially B-cell acute lymphoblastic leukemia, embodies how encouraging this restorative method can be for treating other nonhematopoietic cancers. Till date, the majority of scientific interventions have been conducted to address the hematopoietic malignancies. This review impels the requirement for directing further research concerning the nonhematopoietic malignancies and adds on more to the current information based on anticancer treatments.

Keywords: Adoptive cell transfer therapy, chimeric antigen receptor T-cells, immunotherapy


How to cite this article:
Ahmad F. Chimeric antigen receptor T-cell therapy in hematopoietic and nonhematopoietic malignancies. Biomed Biotechnol Res J 2020;4:179-85

How to cite this URL:
Ahmad F. Chimeric antigen receptor T-cell therapy in hematopoietic and nonhematopoietic malignancies. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Dec 5];4:179-85. Available from: https://www.bmbtrj.org/text.asp?2020/4/3/179/294861




  Introduction Top


For a considerable number of years, cancer has been majorly addressed by the means of surgical interventions, chemotherapeutic agents, and exposing the affected cells to irradiations. With further advanced research, cancer therapies leveraging medications such as imatinib and trastuzumab have evolved as effective therapeutic agents and thus have gained lots of importance in the past 20 years. They incorporate certain molecular transformations in correspondence to cancer cells.[1] With the advent of latest technologies, researchers have developed effective anticancer treatments, such as immunotherapy and adoptive cell therapy. Immunotherapy has been found to be highly beneficial as it functions by boosting the immunity of the affected individual to combat and destroy the cancer cells. With the passage of time, adoptive cell transfer (ACT) therapy has evolved as one of the most sought-after immunotherapies. This therapeutic technique involves the collection of the immune cells of the affected individuals and then utilizes the same cells for treating cancer. The ACT therapy is accomplished by using tumor-infiltrating lymphocytes, T-cell receptors (TCRs), or chimeric antigen receptors (CARs). Among these three kinds of ACTs, maximum scientific advancement has been witnessed in the case of CAR.[2]

Moreover, CAR-T therapy is a unique therapeutic method for treating cancer as it primarily employs genetic engineering tools to modify the T-cells collected from the patients to produce specific transmembrane proteins on the surface of T-cells accompanied with the production of extracellular antibody fragment domain, which identifies a specific protein and subsequently uses these genetically modified cells for therapeutic purpose.[3] CAR-T therapy involves isolation of the T-cells from the blood of the affected individual or any donor by the means of leukapheresis. The isolated T-cells are subsequently subjected to genetic engineering techniques for the development of the CARs on the cell surface, which finally results in the production of CAR-T cells. The CAR-T cells are then cloned under the standard laboratory conditions and are introduced in the blood of an affected individual. The CAR-T cells act by detecting the cancer-affected cells through recognition of cancer-specific antigens present on the surface of cancer cells.[4] At present, the procedures involved in CAR-T cell therapy take approximately 2–3 weeks. To address this gap of several weeks for the accomplishment of the therapeutic process, the affected individual is subjected to chemotherapy. Before the introduction of CAR-T cells, special kind of chemotherapy is given to the patient which primarily involves the destruction of lymphocytes to prevent the existing lymphocytes to compete with the newly introduced genetically engineered lymphocytes. The proliferation of CAR-T cells is marked with the release of cytokines. One of the significant drawbacks of this therapeutic technique is the development of cytokine release syndrome that results from excessive production of cytokines by the CAR-T cells. They consequently lead to an increase in the body temperature, lowering of blood pressure, problems associated with respiration, neurotoxicity, and also other negative outcomes, such as headache and anxiety.[4]


  Construction of Chimeric Antigen Receptor Top


The CAR is an amalgamation of antibody and partly TCRs and is made up of the extracellular antigen-binding domain and intracellular signaling domain. The genetic modification of a T-cell using CAR is done by the means of the single-chain variable fragment (scFv), which is primarily derived from an antibody specific to a tumor tissue. The scFv helps in attachment of the T-cell to the tumor antigen. This allows triggering of T-cells by the CD3ζ ITAM domains within the cells. To obtain the CAR gene construct in complete form, a hinge along with a transmembrane domain connects the extracellular scFv and the intracellular CD3ζ ITAM domains.[5]


  First-Generation Chimeric Antigen Receptor T-Cells Top


From previousin vitro experiments, it can be inferred that CAR-T cells possess an intracellular domain for transmitting signals that are primarily made up of CD3ζ. These cells are also termed as first-generation CAR-T cells. These cells possess extremely restricted constancy and antitumor adequacy in vivo. However, one of the principle preferences to the CAR innovation is its secluded nature; it enables ceaseless refinement and alteration to streamline T-cell work, which is the way the original CARs were supplanted with the second-generation CARs.[6],[7] The TCR showcases its specificity against a short peptide chain (8–12 amino acids) derived from the foreign antigen. Thus, there exists a possibility of cross-reactivity mechanisms taking place considering similar peptide sequences.

In view of fact that the TCR ligation of host antigen could prompt T-cell initiation, autoimmunity, and even demise, there exists a requirement of two types of signals for completely activating the T-cells. The first signal is transmitted through the TCR, yet the second signal, or co-stimulation, is interceded through ligation of CD28 by CD80 or CD86, which are regularly produced on the surface of the antigen-presenting cells (APCs).[8] Thus, on coming in contact with a cross-reactive peptide produced on the surface of an ordinary cell, the T-cell fails to serve for stimulation that prevents activation of the T-cells. In any case, when APCs are initiated, as observed during inflammation or infectious ailments, they upregulate CD80 and CD86 and may lead to the production of both the signals, subsequently supporting full T-cell activation, target executing, and long-haul persistence.[8],[9] CAR examiners along these lines fused the two-signal model of T-cell enactment by adjusting CARs to incorporate a CD28 costimulatory space coupled with CD3ζ ITAM domains. Such second-generation CARs favorin vitro activation of T-cells and destruction of cancerous cells and also majorly favor adequatein vivo destruction of tumor cells and T-cell persistence.[8],[9]


  Second-Generation Chimeric Antigen Receptor T-Cells Top


It is evident from the past research activities that CAR-T cells belonging to second generation aid in carrying probable antileukemia responses during Stage 1 clinical examination. On injecting individuals affected with B-cell acute lymphoblastic leukemia (B-ALL) with second-generation CD19-targeted T-cells possessing CAR with a 4-1BB or CD28 costimulatory domain, it was observed that the CR rate surged up to 90%.[10] While extraordinary achievement has been noted with focusing on CD19, there are critical security and liability issues associated with adjusting this innovation in accordance with different diseases. Envisioning these issues, investigators have started looking into the secluded idea of the CAR in addition to refining and upgrading this novel antigen receptors.[11],[12]


  Advancements in Chimeric Antigen Receptors-Modified T-Cell Therapy in Hematopoietic Malignancies Top


CAR-modified T-cells therapy is used to cure various diseases such as myeloma, lymphoma, acute myeloid leukemia (AML), B-cell malignancies, and hematologic malignancies. Clinical trials in B-cell malignancies and non-B-cell malignancies by utilizing the engineered CAR-T cells are discussed below:

B-cell malignancies

B-cell malignancies are the most widely recognized tumor type to be focused by engineered T-cells.[13] The utilization of engineered T-cells to treat B-cell tumors, particularly B-ALL, has demonstrated the best guarantee in the field to date. The extracellular glycoprotein CD19 is the most well-known B-cell target for engineered T-cell treatments. CD19 is communicated on both benign and most malignant B-cells, with a great degree restriction to non-B-cell articulation.[14] A few groups have detailed response rates to CAR-T19 cells in over 80% of patients with relapsed and refractory B-ALL.[14],[15],[16] In addition, a few clinical trials have affirmed that CAR-T19 cells are compelling for treating refractory lymphoma with by and large response rates of 50%–80%.[17] Others have focused on uncommon CD19+ multiple myeloma stem cells, showing disease eradication at a year after an adoptive transfer of CAR-T19 cells.[18]

Non-B-cell malignancies

The successful destruction of B-cell malignancies by engineered T-cells has given the establishment on which the field of adoptive T-cell treatment is growing. To viably target malignant plasma cells in conditions, for example, multiple myeloma, new targets must be considered. One such target, B-cell development antigen (BCMA, otherwise called TNFRSF17), is comparable to CD19 in that it is expressed much of the time of multiple myeloma and is not expressed on nonplasma cells.[19],[20] Dissimilar to CD19, however, BCMA signaling can initiate plasma cell expansion and survival.[21],[22],[23],[24] Cancer-testis antigens, for example, NY-ESO-1, are additionally upregulated on the plasma cell myeloma cells and can be exceptionally immunogenic.[25] Treatment of myeloid malignancies has not advanced significantly over past decades; however, engineered T-cell treatment may change this. Myeloid cell surface markers upregulated on malignant cells (for instance, CD33, CD123 (otherwise called IL3Rα), and CD44 v6) are under scrutiny as T-cell treatment targets.[26],[27] Currently approved CAR-T cell therapy for hematologic malignancies are given in [Table 1].
Table 1: Clinically approved chimeric antigen receptor-T therapy for hematopoietic malignancies

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  Chimeric Antigen Receptor T-Cell Therapy in Nonhematopoietic Solid Tumors Top


Although CAR-T cell therapy is very promising [Figure 1] in the treatment of nonsolid hematopoietic malignancies, it is still in the infant stage for nonhematological tumor management. This is due to the additional challenging situation in nonhematological tumors such as lack of antigen, hostile tumor microenvironment, and poor trafficking of engineered T-cells.[2] The hematological liquid tumors have one common antigen CD19 on all the B-cells, whereas there no such common antigen found in the case of nonhematological tumors.[14],[15],[16] Unlike the hematological malignancies, it is not possible in solid nonhematopoietic tumors to directly infuse the CAR-T cells into the blood. Furthermore, one of the major limiting factors for CAR-T cell therapy in solid tumors is the hostile tumor microenvironment. For instance, the microenvironment of pancreatic adenocarcinoma is highly immunosuppressive which eliminates the engineered T-cells easily, and thus, the efficacy of the T-cells is decreased. To overcome these limitations, the combinational therapies such as phytotherapy and in combination with immunocheckpoint inhibitors can be used along with the CAR-T therapy. In addition, the reduction of the tumor size of solid tumors may increase the efficiency of the CAR-T cell therapy. This can be done by providing CAR-T cell therapy in combination with surgical debulking, radiation therapy, cryoablation, and radiofrequency ablation. In addition, the CAR-T cells may be improved to enhance their efficacy and specificity by addition of chemokine receptors. Chemokines are molecules released by cancer cells for proper trafficking to the tumor site. These receptors of CAR-T cells should be complementary to the chemokine molecules for improvement in the migration of T-cells.[29] Some of the existing clinical trials for the treatment of solid tumors and their current stages are tabulated in [Table 2].
Figure 1: An overall process of chimeric antigen receptor T-cell therapy. Chimeric antigen receptor-T therapy involves isolation of the T-cells from the blood of the affected individual and subjected to genetic engineering techniques for the development of the chimeric antigen receptors on the T-cell surface, which finally results in the production of chimeric antigen receptor T-cells. The chimeric antigen receptor T-cells are then cloned under standard laboratory conditions and are introduced in the blood of the affected individual. The chimeric antigen receptor T-cells act by detecting the cancer-affected cells through recognition of cancer-specific antigens present on the surface of cancer cells

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Table 2: Clinical trials and phases of chimeric antigen receptor-T cell therapy in nonhematopoietic malignancies

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  Persistence and Homing of Chimeric Antigen Receptor T-Cells Top


In the Phase I investigation of autologous CAR hostile to LeY T-cell treatment in AML patients, Ritchie et al., 2013 inspected the security and postinfusion persistence of adoptively exchanged T-cells. Following the fludarabine-containing preconditioning, four patients were found to have 1.3 ×109 aggregate T-cells, of which 14%–38% of cells have communicated CAR.[53] The first patient acquired cytogenetic abatement, while the second patient with dynamic leukemia had shown a decrease in peripheral blood components, and the third demonstrated a protracted remission. Moreover, in the patient with leukemia cutis, CAR-T cells penetrated proven sites of sickness, and the study has also reported that the injected CAR-T cells persisted for 10 months. Utilizing anin vivo“stress test” to challenge CD19-focused on T-cells, Zhao et al., 2013 contemplated the usefulness and constancy bestowed by seven diverse CAR structures. Among which one configuration utilizes two signaling domains (CD28 and CD3ζ) and the 4-1BB ligand that gives the most efficient remedial adequacy, and also make a balanced on tumoricidal function. It also showed prolonged T-cell persistence along with an elevated CD8/CD4 proportion and diminished exhaustion.[54] In other instance, di Stasi et al., 2009 suggested that the co-expression of C-C chemokine receptor type 4 (CCR4) and CD30 on T-lymphocytes can enhance the homing of CAR-CD30-modified T-cells in Hodgkin's lymphoma (a blood cancer that begins in the lymphatic system) and subsequent improvement in its anticancer activity.[55]


  Countering Tumor and Milieu Immunosuppression Top


Induction of an antitumor immune response is a multistep process which is executed by effector T-cells that can identify and kill the specific tumor targets. Most tumors overcome the body's immune response by meddling with the mechanisms required for viable immunity from deregulation of antigen-exhibiting cells to a physical hindrance at the vasculature that avoids homing of effector tumor-destroying cells. Understanding antitumor immunity, and how it ends up incapacitated by tumors, will eventually prompt birth of new ideas for enhanced resistant treatments. Further, Motz and Coukos, 2013 inspected the mechanism by which the tumors cause immunosuppression.[56] Retinoic acid-inducible gene I (RIG-I) is an example of pattern recognition receptor that is initiated by 5′-triphosphate RNA molecules to prompt type I interferon discharge and apoptosis in light of viral infection. In 2013, Schnurr and Duewell reported a bifunctional small-interfering RNA that consolidated the changing growth factor β silencing with RIG-I activation to break tumor-induced immunosuppression.[57] This system indicated helpful in a murine model of pancreatic cancer. They saw that the organization of ppp-TGFβ prompted the entrapment of activated CD8+ T-cells into the pancreatic tumors. In addition, the depletion of CD8+ T-cell annulled the therapeutic efficacy of ppp-TGFβ, indicating the emergence of a therapeutically pertinent adaptive immune response against the pancreatic adenocarcinoma.[53],[57] In this way, the dual activity of ppp-TGFβ seemed to have additive effects on breaking the immunosuppressive milieu built up by pancreatic cancers, tipping the balance toward a successful antitumor-resistant scenario.


  Genome-Edited and Engineered Allogeneic T-Cells for Universal Chimeric Antigen Receptor T-Cell Development Top


Clinical-scale gene-disrupted CAR-T cells with a potent antitumor activity and a reduced alloreactivity can be proficiently produced by multiplex CRISPR technique and may potentially utilized as off-the-shelf universal T-cells as recommended by Ren et al., 2017.[58] This protocol may be consolidated into the current GMP-compliant-manufacturing procedures as it may have a high potential in adoptive exchange treatment of zinc finger nucleases (ZFNs) in HIV/AIDS with other diseases.[59],[60] In spite of all mechanisms, the function might be compromised due to shorter persistence, disturbed gene , and allogeneic CAR and TCR T-cells. Gene-disrupted allogeneic CAR and TCR T-cells with disabled checkpoint molecules may be a strong effector cells against cancers and other infectious diseases.

Torikai et al., 2012 showed that TCRneg CAR + T-cells can be created utilizing a genetic approach to expel (a) endogenous undesired TCR with ZFNs and (b) present a coveted CAR with the SB framework utilizing a typical electrotransfer platform.[61] This strategy gave an imperative advance to build up an “universal” CAR + T-cell which can be fabricated from one donor and administered to numerous patients only with one request. They proposed that resulting studies can be centered around averting dismissal of the implanted allogeneic TCRneg CAR+ T-cells by the beneficiary's immunity system perceiving divergent HLA. This might be refined utilizing genetic modifications including a ZFN-intervened knockout of HLA and over-articulation of saved HLA homologs to repress NK-cell action.


  Conclusion Top


CAR-T cell therapy is highly promising than other conventional anticancer treatments, such as surgical interventions and chemotherapy, as it involves strengthening the immune system of the host and induces immunogenic responses in the host for the destruction of tumors. This therapeutic approach involves isolation of the host T-cells and genetic alterations to render them competent enough to fight against cancer effectively. However, CAR-T cell therapy has been used to treat a range of malignancies. The utilization of genetically engineered T0-cells for treating B-cell tumors, particularly B-ALL, exemplifies how promising CAR-T therapy can be for treating cancerous cells. Till date, the majority of scientific interventions have been conducted to address the hematopoietic malignancies. This instigates the need for conducting further research concerning the nonhematopoietic malignancies and adds on more to the existing knowledge base on anticancer therapies.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Introduction
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Second-Generatio...
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