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 Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 1  |  Issue : 2  |  Page : 86-90

Chimeric antigen receptor T-cell therapy in the treatment of acute myeloid leukemia: Possible challenges


1 GMERS Medical College, Gandhinagar, Gujarat, India
2 Datta Meghe Institute of Medical Sciences, JNMC, Wardha, Maharashtra, India
3 Guntur Medical College, Guntur, Andhra Pradesh, India
4 Rangaraya Medical College, Kakinada, Andhra Pradesh, India
5 Dr. NTR University of Health Sciences, Vijayawada, Andhra Pradesh, India

Date of Submission13-Aug-2021
Date of Decision05-Sep-2021
Date of Acceptance13-Sep-2021
Date of Web Publication22-Dec-2021

Correspondence Address:
Mr. Tarun Kumar Suvvari
17-2-49/2, Vengala Rao Colony, Amadalavalasa, Srikakulam - 532 185, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/aort.aort_18_21

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  Abstract 


Cancer, which is considered one of the most dangerous diseases, can arise from any part of the human body. We are still lacking the effective and curable treatment modalities for many cancers that can affect the life of patients adversely. One such is acute myeloid leukemia (AML) that arises from the myeloid cells due to the somatic gene mutation that can disturb that particular cell lines or many cell lines together, thus causing overcrowding or inhibitory suppression of bone marrow. The biggest challenge that we are facing in terms of AML is not having an effective cure and increasing rates of relapse and recurrence. However, one of the therapeutic methodologies that are emerging nowadays is the chimeric antigen receptor T-cell (CAR T-cell) which have shown promising results, especially in the case of acute settings such as acute lymphoblastic leukemia and few relapsed cancers such as Ph negative ALL and multiple myeloma. CAR T-cells are the types of living drugs that are prepared from the T cells of patient's bodies and are cultured and grown artificially in the laboratory. They are also provided with artificially engineered receptors so that they identify the specific cancerous cells and kill only them without harming normal cells. No matter how novel it may sound, this modality is also not free from side effects, and some of the severe ill effects have been described and reported with the usage of CAR T-cells. Some of them may include severe cytokine storms, toxicities and failed treatment. Thus, we need to improvise on our techniques and there is a huge scope of future research in making CAR T-cells an effective and regular treatment option for patients suffering from AML.

Keywords: Acute myeloid leukemia, blood cancer, chimeric antigen receptor T-cells


How to cite this article:
Mittal RJ, Adhit KK, Vakkalagadda NP, R. Salibindla DA, Suvvari TK. Chimeric antigen receptor T-cell therapy in the treatment of acute myeloid leukemia: Possible challenges. Ann Oncol Res Ther 2021;1:86-90

How to cite this URL:
Mittal RJ, Adhit KK, Vakkalagadda NP, R. Salibindla DA, Suvvari TK. Chimeric antigen receptor T-cell therapy in the treatment of acute myeloid leukemia: Possible challenges. Ann Oncol Res Ther [serial online] 2021 [cited 2022 Aug 8];1:86-90. Available from: http://www.aort.com/text.asp?2021/1/2/86/333303




  Introduction Top


Cancer has been considered one of the deadliest diseases present on the planet for several decades. Cancer is a disease, in which the cells inside the body divide without any restrictions and are uncontrollably out of proportion to the normal cells.[1] Normally, the new cells are formed, grow old, and finally, die and again form new cells as and when required. Sometimes, this orderly process breaks down, and the abnormal and damaged tissue instead of dying starts to grow and form cancerous cells and tumors.[1] There are more than 100 types of cancers, and they are named according to the organ or tissue they arise from. For instance, lung cancer starts in the lungs and leukemia starts in the blood. Leukemia is a tumor that begins in the blood-forming tissue of the bone marrow. They do not form solid cancers, but a large number of abnormal cells proliferate and build up in bone marrow, thus crowding out the normal cells. There are four common types of leukemia which are based on how rapidly the disease gets worse that is acute or chronic and from where they are arising which is lymphoid or myeloid. There are various modalities of detecting blood cancers such as physical examinations, various physicians look for various signs of leukemia such as anemia swelling of lymph nodes and enlargement of liver and spleen Blood tests and bone marrow tests are other modalities available for diagnosis.[2],[3]

Treatment modalities at present available are chemotherapy which is the major form of treatment, in which drugs are used to kill the leukemia cells. Whether you will receive a single drug or combination of drugs will depend on the type of cancers you have which may come in the form of pills injections or powders. Another is the targeted drug treatment which focuses on the specific abnormalities in the cancer cells radiotherapy, immunotherapy, engineering immune cells to fight leukemia, and stem cell transplant are few other modalities of treatment. However, the crux of the matter is none of them are conclusive and there are high reports of relapse and recurrence, thus further complicating the matter.[1],[2],[3]

One such type of leukemia is acute myeloid leukemia (AML), which is one of the most common types of blood cancer worldwide and multiple treatment options have been tried on that also but the problem of recurrence and relapse hold for AML. One modality of treatment that has shown promising effects and providing hope is chimeric antigen receptor (CAR) T-cell therapy.


  Chimeric Antigen Receptor-T Cell Therapy Top


CAR T-cell therapy is a very promising therapy that can cure certain types of cancer with high success rates in a much more efficient manner when compared to its counterparts present in the market such as chemotherapy and radiotherapy. The main problem of chemotherapy is that its side effects are dangerous and everlasting with complications ranging from permanent hair loss to impairment of various systems of the human body. CAR T-cell therapy especially remains one of the most promising treatment modalities for various hematologic malignancies. It has also been approved for the relapsed or recurrent cases of diffuse large B-cell lymphoma, Ph negative ALL, and multiple myeloma. The treatment time is also very short when compared to other treatments. CAR T-cells can easily reach the central nervous system (CNS) and they help in the clearance of CNS disease.[4],[5]


  Living Drug Top


CAR T-cells are just equivalent to the living drug or rather chemotherapy to the patient because as we know chemotherapeutics work on the specific cell or the diseased cell and remains ineffective to the normal or healthy cell; in the same way, cart cells go and attack the leukemic cell while sparing the normal cells. However, since they are actively metabolizing cells and are derived from patients' bodies, so they are called living drugs. As indicated in the name CAR T-cells, the main component is the T-cell which are the workhorses of the immune system because of their function of killing the intracellular pathogens that escape the humoral immune system; thus they are one of the most important cells of the immune system in the body.[4],[5] The process of CAR T-cells working as described in [Figure 1].
Figure 1: Flow chart describing how chimeric antigen receptor T cells works

Click here to view


During CAR T-cell therapy, the cells are drawn from the blood of the patient and T-cells are separated. This process of separation of T-cells is called product manipulation. The physician chooses the appropriate window for the collection of blood based on the treatment regimen to have enough T-cells and they are collected through the leukapheresis process. After that, they can be processed in various ways depending on the downstream procedures.

Devices such as hemonetics cell saver 5+, COBE2991 can remove the gross RBC and platelets. Biosafe Sepax systems provide size-based cell fractionations for removing monocytes and isolating lymphocytes. Following which instruments such as CliniMACS Plus and Prodigy system allow the isolation of a specific subset of T-cells such as CD4+ and CD8+.[11] Next, using the non-harmful viruses, specific genetically engineered receptors are created on the surface of the T-cell which is synthetic receptors as they are normally not present on the T-cell and this is called chimeric antigen receptors.[4]

The most commonly used viral vector is the murine leukemia virus and was successfully used in T-cell immunotherapy for SCID. Other examples include lentivirus and gamma retroviral vectors.

Viral vectors are highly efficient in the manufacturing of CAR T-cells. However, they have got some limitations such as high cost of production, oncogenic and mutagenic potential, their transduction is limited by the size of transported DNA, and also for their production laboratories have to follow a set of strict restrictions to prevent them from contamination.[12] These receptors help the cart cells to attach to the specific antigen or protein or sequence present on the tumor cell and thereby killing them specifically. Once the T-cell is genetically engineered and give chimeric antigen receptors, these are multiplied in hundreds of millions in the laboratory to get the correct effective dose for the patient.[5] Finally, the cells are infused into the patient's body and if everything goes completely alright they will further multiply inside the patient's body, and then with the help of chimeric antigen receptors, they kill the tumor cell only. Some of the prerequisites to home CAR T-cell in the bone marrow are:

  • The tumor should express a CAR antigen such as CD 19, CD20, and CD21
  • Adequate quantity of T-cells for collection
  • No active and uncontrolled infections such as hepatitis B and C HIV
  • Adequate performance status and no clinically relevant comorbidities.


These were initially developed for the pediatric all whose treatment after the recurrence even after giving stem cell transplantation is none. Hence, it gave everyone hope when there is nothing left to do in such aggressive cancer that can kill the patient in days if no further treatment is given.[5],[6] The entire process from preparation CAR T-cells to the introduction of CAR T-cells into the human body was described in [Figure 2].
Figure 2: Flow chart describing the entire process from preparation chimeric antigen receptor T cells to introduction of chimeric antigen receptor T cells into the human body

Click here to view



  Adverse Effects of Chimeric Antigen Receptor-T-cell Therapy Top


Similarly, any other cancer treatment in the world, the cart cells also come with advantages and side effects of their own, the most severe being the cytokines release syndrome. But is cytokine release syndrome (CRS) that bad?

CRS generally refers to the group of symptoms that occurs due to abnormal activation of the immune cells that cause the release of cytokines in huge amounts in the body.

To this date, the most prevalent side effect of CAR T-cell therapy is the CRS. CRS can be characterized by elevated inflammatory cytokines, and it can range from mild CRS to server CRS, in which various organ dysfunctions can also be seen.

Some of the cytokines that show marked elevation following CRS due to CAR T-cell infusion are interferon-gamma, granulocyte-macrophage colony-stimulating factor, interleukin-10 (IL-10), and IL-6.

It may be very much important to identify and measure these markers as the presence of CRS can correlate with the expansion and immune activation of the transferred cells. Apart from this, the severity of CRS that the patient develops also correlates with the disease burden at the time of infusion.

CNS CRS is called immune effector cell-associated neurotoxicity syndrome, and they are generally characterized by delirium, aphasia, and seizures, but most of the time, it is reversible.[13]

They are not that bad because these cells while fulfilling their duty of killing pathogens and microbes release the cytokines and other chemical messengers to effectively kill the pathogen or tumor cells, but in CRS, there is a massive amount of cytokines released in the bloodstream that can affect the patient adversely.[7],[8] However, releasing cytokines in the way also shows that the cart cells are doing their job as it has been observed that patient who has more severe/extensive diseases before this therapy is at increased risk of getting CRS. However, the CRS can be effectively managed by the standard therapy such as steroids or tocilizumab, but at the same time, these drugs will decrease the efficacy of the cart T-cell also as they depress the immune system also, so use them only in the condition where the patient is not able to tolerate the therapy.[7],[8] More recently, some other side effects of this therapy have been found such as cerebral edema which is the fatal side effect, so-called neurotoxicities confusion and seizures like activities have also been detected.[5]


  Prevention and Management of Adverse Effects Due to Chimeric Antigen Receptor T-Cells Top


As we all that the CAR T-cells must remain in their therapeutic range to be clinically effective because if they overshoot their function it leads to CRS and then we have to suppress the cart cells by giving steroids and tocilizumab, thus decreasing their response. From various studies, it is clear that various factors affect them including but not limited to the types of antigens expressed on the tumor cells, tumor burden, malignant potential, costimulatory elements. Therefore, careful consideration of cart cells is required to limit their toxicity and increase their efficacy.[7],[8] One way of doing this is by altering the affinity of cart cells to bind to the antigen. Others may include processes such as modifying the hinge and transmembrane regions. Another region that offers a modifiable forum/arena is the CO stimulatory region. Thus, using all these modifications, we can expect to make the cart cell therapy less toxic and better tolerated by patients.[8]


  Discussion Top


Cancer is the serious health-care issue that we are facing have only a few treatment modalities such as chemotherapy, radiotherapy, or immunotherapy, and they are not always effective due to fewer cure rates or increasing number of relapse and recurrence.[7],[8] However, CAR T-cell is one very efficient and promising therapy that can help us cure some the cancers such as AML. They are much more effective in comparison to their other counterparts such as radiotherapy and chemotherapy.

Hematological indications of CAR T-cells that are approved are CD19 in ALL, CD79a in diffuse large B-cell lymphoma, and BCMA in multiple myeloma.

Regarding the effectiveness of CAR T-cells in solid tumors, a humanized TAG72-specific cart cells have significantly decreased the proliferation potential and argumentation in some trials on mice. Another in vitro trial also showed that MUC16-Specific cart cells could decline the ovarian cancer progression completely or eradicate the malignant cells in a mouse model. Other studies have also shown that their work can be extended into prostate cancer, gastric cancer, renal cancer, pancreatic cancer, lung cancer, liver cancer, and colorectal cancers. However the research is still going on, and these methods are still in the development phase and no clear-cut guidelines are available on them. But if they prove to be effective, then they can change the way we look at the treatment of these solid tumors today. However, the few challenges that researchers are facing in using cart cell therapy in solid tumors are factors such as tumor antigen heterogeneity which impairs the detection of tumor cells by cart cells and thus decreases the efficiency and efficacy of the cells.[9]

During CAR T-cell therapy, the T-cell is drawn from the patient's own body and then after separating them from other components of blood known process called product manipulation, they are isolated and purified. Next, using nonharmful viruses' synthetic receptors are created on the following which they are grown and multiplied in hundreds of millions in the laboratory. They are finally infused into the patient's body for the treatment of AML.[10]

Some of the reliable tumor target antigens against which CAR T-cell therapy has been developed are GD2, LGR5, IGF-IR, CD44, CD47, EpCAM, D114, FZD, and CD123.[11],[12],[13],[14]

One of the major challenges of trying CAR T-in AML is the absence of a single target, particularly in the relapse setting. AML is a heterogeneous disease comprising continuously acquired genetic abnormalities over a long time. This is the main reason why the concept of CAR T-cell therapy in AML may not be feasible. Further, given the short life of viral vectors, accomplishing a sustained blockade of any one target may not be possible. In theory, at least, CAR T-cell is not an immediate possibility in the management of AML. Thus, thorough research is required in this particular field before it is available to patients so that we can achieve the desired clinical results. The CAR T-cell was one of the effective and promising modalities which are in great limelight among the scientists because of its ability to treat cancers and also its greater usage in relapse and recurrence cases, but these modalities are also not entirely free from side effects, and some severe side effects such as cytokine Strome have been reported, thus needing further research to implement CAR T-cell in the routine cancer treatment.[7]


  Conclusion Top


CAR T-cells are the example of the best-in-class genetic engineering of T-cells bringing in amazing opportunities and hopefully entering the mainstream of cancer treatment. However, as every coin has two faces there is no exception for this therapy also and there are few shortcomings in the CAR T-cell therapy which can be considered as a novel modality. Moreover, a similar response has not been observed in the treatment of solid tumors due to less efficacy and on-target/off-tumor toxicities. However, the eventual effects of these novel designs still need to be determined in the forthcoming clinical trials.

Acknowledgment

Sincere Thanks to Squad Medicine and Research for their support and guidance. I would also like to extend my heartfelt thanks to Yasmin Farah Peer, Concordia University, Political Science and Human Rights and Lives for Literacy for their diligent English and Grammar proofreading of this paper.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
What is Cancer? National Cancer Institute. Available from: https://www.cancer.gov/about-cancer/understanding/what-is-cancer. [Last accessed on 2021 Jul 30].  Back to cited text no. 1
    
2.
Car T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. National Cancer Institute. Available from: https://www.cancer.gov/about-cancer/treatment/research/car-t-cells. [Last acessed on 2021 Jul 30].  Back to cited text no. 2
    
3.
Leukemia. Mayo Clinic. Available from: https://www.mayoclinic.org/diseases-conditions/leukemia/diagnosis-treatment/drc-20374378. [Last accessed on 2021 Jul 30].  Back to cited text no. 3
    
4.
Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol 2019;94:S3-9.  Back to cited text no. 4
    
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Sterner RC, Sterner RM. CAR-T cell therapy: Current limitations and potential strategies. Blood Cancer J 2021;11:69.  Back to cited text no. 5
    
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Kenderian SS, Porter DL, Gill S. Chimeric antigen receptor T cells and hematopoietic cell transplantation: How not to put the CART before the horse. Biol Blood Marrow Transplant 2017;23:235-46.  Back to cited text no. 6
    
7.
Wang Z, Wu Z, Liu Y, Han W. New development in CAR-T cell therapy. J Hematol Oncol 2017;10:53.  Back to cited text no. 7
    
8.
Rohit Reddy S, Llukmani A, Hashim A, Haddad DR, Patel DS, Ahmad F, et al. The role of chimeric antigen receptor-T cell therapy in the treatment of hematological malignancies: Advantages, trials, and tribulations, and the road ahead. Cureus 2021;13:e13552.  Back to cited text no. 8
    
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Marofi F, Motavalli R, Safonov VA, Thangavelu L, Yumashev AV, Alexander M, et al. CAR T cells in solid tumors: Challenges and opportunities. Stem Cell Res Ther 2021;12:81.  Back to cited text no. 9
    
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Miliotou AN, Papadopoulou LC. CAR T-cell therapy: A new era in cancer immunotherapy. Curr Pharm Biotechnol 2018;19:5-18.  Back to cited text no. 10
    
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Wang X, Rivière I. Clinical manufacturing of CAR T cells: Foundation of a promising therapy. Mol Ther Oncolytics 2016;3:16015.  Back to cited text no. 11
    
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Lukjanov V, Koutná I, Šimara P. CAR T-cell production using nonviral approaches. J Immunol Res 2021;2021:6644685.  Back to cited text no. 12
    
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Bonifant CL, Jackson HJ, Brentjens RJ, Curran KJ. Toxicity and management in CAR T-cell therapy. Mol Ther Oncolytics 2016;3:16011.  Back to cited text no. 13
    
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Masoumi J, Jafarzadeh A, Abdolalizadeh J, Khan H, Philippe J, Mirzaei H, et al. Cancer stem cell-targeted chimeric antigen receptor (CAR)-T cell therapy: Challenges and prospects. Acta Pharm Sin B 2021;11:1721-39.  Back to cited text no. 14
    


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