Chimeric Antigen Receptor T-Cell Therapy: Overview

The use of novel immunotherapy, such as the chimeric antigen receptor (CAR) T-cell therapy, for the treatment of cancer has revolutionized the way that patients with cancer are treated. These treatments are creating new and exciting possibilities for patients who otherwise may not have had other viable treatment options. Historically, chemotherapy has been the mainstay of systemic therapy for most cancer patients. Unfortunately, chemotherapy can cause significant and sometimes debilitating toxicities that in some cases may last a lifetime. Although the use of CAR T-cell therapy is an available standard-of-care treatment for select patients, not all cancer patients derive a benefit from it. In May 2018, the FDA approved the use of axicabtagene ciloleucel and tisagenlecleucel for the treatment of adult cancer patients with aggressive high-grade CD19-expressing diffuse large B-cell lymphoma and acute lymphoblastic leukemia in whom 2 or more lines of therapy have failed and/or in patients who have relapsed disease after undergoing stem cell transplant.^1,2 In clinical trials, patients with primary central nervous system lymphoma were excluded and thus not indicated in this group of patients. For some patients, the use of CAR T-cell therapy has resulted in robust and durable (>95%) responses lasting longer than 5 years.^1,2 These responses have not previously been observed in patients in whom 2 or more prior chemotherapy lines or targeted therapies have failed. Although axicabtagene and tisagenlecleucel are the only 2 FDA-approved agents on the market for clinical use, other agents, including Liso-cel, are currently under investigation in clinical trials for patients with liquid and solid tumors, including brain tumors, and lung and ovarian cancers.¹ In this article, we present an overview of CAR T-cell therapy and clinical implications.

What Are CAR T-Cells?

T-cells are part of the body’s innate immune system and are responsible for immune surveillance and destruction of abnormal cells, including infections and cancer cells. T-cells possess protein receptors on the cell surface that have claw-like structures that enable them to latch onto foreign fragments, also known as antigens. When working properly, T-cells are able to mount an attack by releasing toxic substances.^2,3 Unfortunately, in some cases, T-cells lose this function and the ability to recognize and mount an attack on abnormal cells, resulting in proliferation of abnormal cells and/or cancer cells. CAR T-cells are synthetic protein receptors that are found on the cell surface. The CAR is the portion of the cell that is genetically modified in the laboratory, and, when introduced into the T-cell, becomes highly activated and capable of recognizing and destroying cancer cells.

Immune System Tumor Evasion: How Do Cancer Cells Evade the Immune System?

Optimizing safety and improving treatment outcomes are 2 major goals of cancer treatment. Cancer researchers have continued to explore and gain understanding of how cancer cells behave, including resistance mechanisms that lead to poor outcomes in patients with cancer. These advances have led to the recognition of abnormal pathways that cancer cells use to evade the body’s immune system. One way is by an overexpression of antigens on the surface of cancer cells that makes it difficult for T-cells to effectively mount an attack. Cancer cells can also disguise and masquerade as normal cells and often turn off the immune response to some extent.^2,3 These are likely not the only mechanisms by which cancer cells can evade the immune system. However, this available knowledge provides insight and a basis for possible therapeutic targets for clinical interventions. CAR T-cell therapy has opened a window into other possible adoptive cell therapies for the future and the feasibility of applying these types of treatment across many different types of cancers.

How Does CAR T-Cell Therapy Work?

CAR T-cell therapy is a type of immunotherapy that uses a patient’s own immune T-cells to fight cancer cells. This is achieved through a series of complex processes that utilizes the transfer of CAR genes (gene transfer technique first developed in the 1990s) to reprogram a patient’s own T-cells to recognize and destroy cancer cells by targeting and binding to tumor-associated antigens.^1,2,4 The initial process begins with the removal/separation of T-cells from a patient’s own blood through a process known as leukapheresis. The separated T-cells are expanded or multiplied in vitro, and through a complex process known as transduction, the CAR gene is introduced into T-cells using a vector to produce millions of new T-cells. Typically, an inactive lentivirus or retrovirus is used to introduce genetic information into the T-cells with the goal of increasing tumor cell kill.^2-5 These T-cells are infused back into the patient and undergo extensive proliferation, and when activated, are capable of rendering a lethal attack on cancer cells and have the potential to reduce relapses in these patients. Prior to reinfusion of T-cells, patients receive lymphodepletion therapy with chemotherapy. The goal is to create an environment that is optimal for CAR T-cell proliferation.⁶ Common lymphodepleting agents include fludarabine and cyclophosphamide. These agents are generally administered over a 3-day period starting on day 5 (day minus 5). The length of the entire process from leukapheresis (T-cell harvest), manufacturing, to reinfusion of the T-cells into the patient varies. In general, it may take anywhere from 2 to 6 weeks or longer, depending on several factors, which may include the approval process for the treatment by insurance companies. Treatment responses to CAR T-cell therapy have been observed as early as 3 months from reinfusion of the T-cells. Because of the risks that are associated with CAR T-cell therapy, patient selection is critical. These patients must undergo extensive screening to minimize life-threatening incidences and morbidity and mortality. A CAR T-cell therapy Risk Evaluation Mitigation Strategy must be in place when selecting patients and strictly adhered to during and after treatment.

Indications

Axicabtagene and tisagenlecleucel are the 2 anti- CD19 CAR T-cell therapy agents currently available on the market. They have been approved for patients with aggressive and/or refractory CD19-expressing B-cell lymphoma and refractory acute lymphoblastic leukemia in whom 2 or more treatments have failed, or in patients who have relapsed after stem cell transplant. In 2017, tisagenleucel was approved by the FDA for use in pediatric patients aged 25 years or younger.^7,8 Axicabtagene ciloleucel was approved for use in adult patients with relapsed refractory/aggressive CD19-expressing diffuse large B-cell lymphoma in 2017. This was followed by the approval of tisagenleucel in 2018 for adult patients with acute lymphoblastic leukemia based on the ZUMA-I study that showed progression-free survival of 30% to 40% in this group of patients.⁹ CAR T-cell therapy is administered as a 1-time infusion. Both agents work by targeting both normal and abnormal cells that express the CD19 molecule found on the cell surface. The choice of which agent to use is based on provider preference as there are no specific criteria recommended in this regard.^1,2

Managing Toxicities Associated with CAR T-Cell Therapy

Patients receiving CAR T-cell therapy present with a different toxicity profile, and it is therefore important to identify and mitigate these toxicities to limit morbidity and mortality. Clinicians treating these patients must exercise prudence and vigilance. Unlike chemotherapy, many toxicities associated with CAR T-cell therapy are referred to as on-target effects. These toxicities are generally reversible when the target cell is eliminated and/or if engraftment of the CAR T-cell is terminated.² Two major classes of toxicities have been observed with CAR T-cell therapy. They include the cytokine-release syndrome (CRS) and neurotoxicity (CAR T-cell–related encephalopathy syndrome [CRES]), also referred to as immune effector cell–associated neurotoxicity syndrome. They are discussed elsewhere in detail in this article. The onset of symptoms associated with CAR T-cell therapy varies, with some occurring within minutes to hours after the infusion, whereas others may manifest later. Although rare, other on-target and off-tissue or tumor toxicities have been reported that can persist for years after infusion of CAR T-cell therapy.^1,2,4,10 Management strategies must therefore be tailored to the patient based on presenting signs and symptoms and the patient’s overall clinical condition.

CRS

CRS is a marked systemic inflammatory response that results in a significant release of and elevation of inflammatory cytokines in cancer patients receiving CAR T-cell therapy.^1,10 The development of CRS has been associated with several clinical and laboratory findings. A large disease burden, typically measured by the number of blast cells in the bone marrow of patients with acute lymphocytic leukemia and lymphoma, and the dose of CAR T-cells have been observed to increase the risk. Furthermore, elevated serum cytokines and ferritin have been observed to be predictors of severe forms of CRS. Peak C-reactive protein levels have a direct correlation with CRS and can therefore be used as a surrogate marker for early treatment. Approximately 27% to 64% of patients receiving CAR T-cell therapy will experience CRS of varying degrees.¹¹ Generally, patients present with mild symptoms that progress quickly. These symptoms may include fever or flu-like symptoms, rash, hypoxia, hypotension, diarrhea, hemorrhagic colitis, myelosuppression requiring blood transfusion, and extreme fatigue or malaise. In severe and complex cases, irreversible end-organ damage, including cardiac, liver, and renal failure, and death may occur.^1,4 Identification of these potential complications and early intervention is critical to reduce morbidity and mortality associated with this therapy. Consensus management guidelines recommend managing these toxicities based on the CRS grading criteria. The CRS grading criteria include an assessment of the patient’s hemodynamic state, the degree of hypoxia if present, any organ damage, and the patient’s underlying comorbid state. Patients with grade 3/4 CRS and those with grade 2 but with significant comorbidities should be treated aggressively in an intensive care setting. These patients will generally require vasopressors, steroids, and anticytokine therapy with agents such as tocilizumab, an anti–interleukin-6 (IL-6) receptor, and siltuximab, an anti–IL-6 antibody.^1,10 Because CAR T-cell therapy can lead to B-cell aplasia, patients who develop this condition will often require periodic infusions of antibodies that are normally produced by B-cells. Interestingly, CRS is generally not observed in patients who do not respond to CAR T-cell therapy.

Neurotoxicity

Neurotoxicity, also referred to as CRES, is a common complication associated with CAR T-cell therapy and may often overlap with CRS. Although the pathogenesis is not well understood, cytokines have been observed to be the drivers of this condition.¹¹ During the initial stages, symptoms may be subtle. However, patients may present with confusion and disorientation, headaches, difficulty speaking, and in severe cases, delirium, obtundation, cranial nerve abnormalities, cerebral edema, and seizures, which can lead to death.^1,4,10 Early identification and intervention of these symptoms are critical. A number of neurocognitive assessment tools are recommended to be incorporated in the care of these patients as part of standard of care. These include the Mini-Mental Status Evaluation and CRES assessment tools. Unlike CRS, the use of anti-IL agents has not been established and is therefore not recommended as part of routine standard management in patients who develop neurotoxicities. The use of corticosteroids is the gold standard for managing neurotoxicity. Because these patients can deteriorate quickly, brain imaging with either a CT scan or MRI, lumbar puncture to assess cerebral spinal fluid, and EEG should be obtained to rule out other causes, as appropriate. The risk of developing neurotoxicity is increased in patients who present with a high tumor burden at baseline and elevated lactate dehydrogenase and ferritin levels. It is important that measures to reduce poor outcomes in these patients are considered prior to initiation of treatment. Patients must be selected carefully and monitored closely during and after treatment to reduce the inherent risks associated with CAR T-cell therapy. When patients present with symptoms, treatment must be initiated promptly. A key component of treating patients successfully with CAR T-cell therapy is the inclusion of patient education, and the importance of this cannot be overstated.

Predictors of Response

Although this article is focused on the adult population in general, pediatric patients with acute lymphoblastic leukemia have better outcomes than their adult counterparts. Several factors have been associated with these poor responses in adults. As previously noted, disease burden at presentation plays a major role, with those patients presenting with less than 5% of leukemia cells in the bone marrow deriving the most benefit. This group of patients has also been shown to enjoy long-term remissions in contrast to those patients with high disease burden who have been observed to have higher rates of relapse.⁸ In addition, patients who present with stable disease at the time of CAR T-cell infusion have also been observed to have better outcomes.

Current Challenges

All cancer treatments present with unique challenges and associated treatment toxicities of varying degrees. For most therapies, cure remains elusive. CAR T-cell therapy is not an exception and also presents with unique challenges. Aside from the inherent risks that are associated with this type of treatment, cancer researchers continue to explore ways to prevent relapses associated with antigen loss, which occur at a rate of about 50%.¹ Incorporating CAR T-cell therapy as part of standard-of-care therapy across all malignancies, and integrating this therapy with other cancer immunotherapies, chemotherapy, surgery, and radiation therapy, are under investigation. Although practice changing, broad use of CAR T-cell therapy is limited to large academic and university centers and teaching hospitals. Furthermore, the cost of CAR T-cell therapy is potentially prohibitive. Current estimates for the 1-time treatment range in excess of $400,000, with the bulk, approximately $375,000, allocated to CAR T-cell production alone and excludes other costs before, during, and after hospitalization.¹ Clearly, the economic and financial impact of CAR T-cell therapy borne by the patient, insurance provider, and hospital institution cannot be overlooked.

References

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