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Chimeric antigen receptor therapy (CAR T therapy)

Developed for relapsed and refractory acute lymphoblastic leukemia (ALL) for both adult and pediatric patients.

Chimeric antigen receptors (CARs) have been used to redirect the specificity of T cells against a number of hematologic cancers.

Its beneficial aspect is that treatment is administered once, although the process is a lengthy one.

CAR therapy associated with sustained responses in refractory/resistant DLBCL.

CAR therapy associated with sustained responses in refractory/resistant CLL.

T cells are engineered and genetically modified to recognize B cells and destroy them in B-cell ALL.

T cells  are transduced with a synthetic tumor antigen target receptor, the Chimeric antigen receptor.

The Chimeric antigen receptor is constructed of a tumor antigen recognizing antibody, a single chain variable fragment comprising the heavy and light chain, as well as a flexible peptide linker, a transmembrane domain, and the signaling domain of a T cell receptor.

T cells are harvested through leukapheresis, followed by T-cell activation on antibody-coated beads serving as artificial dendritic cells.

Following CAR T cell collection, T-cell receptor activation, and genetic engineering via retro viral or lentiviral transduction occur.

After CAR T-cell cells are generated, they are expanded to relevant numbers and undergo quality-control testing and are cryo-preserved.

The process involves the collection of the patients T cells, Ex-VIVO genetic modification of the cells to encode a synthetic receptor that binds a specific tumor antigen, and then re-infusion of the cells back into the patient.

CARs are rational dedesigned synthetic receptors that target surface antigens in their native confirmation.

CARs are composed of a tumor targeting moiety, most often antibodies single-chain variable fragment, linked to hinge region, a transmembrane domain, and an intracellular activation motif made up of the CD3 zeta chain of the T-cell receptor complex.

CAR T cells have engineered receptors composed of a cell surface component that binds to a tumor antigen and is attached to one or more internal signal initiators.

CAR T cell therapy relies on the genetic manipulation of a patient’s T cells to generate a response against leukemic cell surface  antigen  most commonly CD19.

Patients receive a three day course of lymphocyte depleting chemotherapy, which generally consist of fludarabine andcyclophosphamide.

The manufacture of CAR T cells requires ex vivo viral transduction, activation, and expansion over several days to weeks to produce is sufficient cell number to engender disease response:Generally  2-4 weeks.

Following infusion, debulking tumors occur in less than a week and these CAR T cells may remain in the body for extended periods of time to provide immunosurveillance against relapse.

Genetic engineering creates a customized T cell that recognizes a distinct protein on cancer cells, bypassing the need for the immune system to fight cancer in its usual ways.

Autologous T cells are genetically engineered to express CARs found on tumor cells as well as on costimulatory molecules.

Activated T cells are genetically reprogrammed by transduction with a construct encoding the CAR, and the CAR T cells are further expanded ex vivo.

Subsequently, the patient receives chemotherapy that is lymphodepleting and CAR T-cell infusion.

Lymphocyte depleting chemotherapy creates a favorable immune environment for CAR -T-cell activity prior to receiving a single intravenous infusion of the product.

The most common method used to introduce the new gene is through viral transfection, either with a retrovirus or a lentivirus.

Following T cell infusion factors that impact their efficacy and toxicity include the extent of previous treatments, intensity of the lymphodepleting chemotherapy regimens, and disease burden at the time of the infusion.

The new gene is integrated into the genome and is transcribed and translated.

The new receptor is now recognized by a target antigen.

The CAR has a targeting domain, typically a single chain variable fragment of an antibody that can target an antigen on a tumor cell.

Two CAR T-cell therapies—tisagenlecleucel and axicabtagene ciloleucel—are now approved by the FDA.

Axicabtagene ciloleucel is indicated for adults with relapsed/refractory large B-cell lymphoma after at least 2 lines of therapy.

Patients with large B-cell lymphoma that is relapsed/refractory after at least 2 lines of therapy have a very poor prognosis, particularly those patients who relapsed within the first year of receiving immunochemotherapy or a stem cell transplant.

CAR T‑cell therapy has been associated with prolonged disease‑free survival for these patients: demonstrating that at more than 4 years post treatment, almost all of the patients who achieved CR remain in remission.

It is critical that the patient’s disease remain stable during the CAR T-cell manufacturing period of 4-6 weeks.

Other agents are effective as bridging therapy: including polatuzumab, ibrutinib, and PD-1 inhibitors.

The patient’s lymphocyte count determines the CAR T-cell manufacturing success rate.

For tisagenlecleucel, an absolute lymphocyte count > 300 cells/mm3 provides approximately 95% manufacturing success, the product of which will be cryopreserved.

Axicabtagene ciloleucel, which remains fresh, requires ≥ 100 cells/mm3.

After confirming that a patient meets these criteria, pheresis and cell manufacturing proceed, with bridging therapy used as necessary in the interim.

When the CAR T-cells are ready, lymphodepletion and cell infusion can be initiated.

Most patients who fail CAR T-cell therapy will progress within the first 3 months.

Patients are at increased risk of infection for up to a year.

If patients can achieve CR and maintain it for 1 year, they have a very good probability of maintaining long‑term, durable CR.

CAR-based therapy is also being tested in relapsed and refractory non-Hodgkin lymphoma, myeloma, and chronic lymphocytic leukemia (CLL), as well as for patients with non-Hodgkin lymphoma and myeloma.

Chimeric antigen receptors are highly specialized, recombinant surface molecules that combine the antigen-recognizing variable region of an antibody in tandem with intracellular T-cell signalling moieties.

CARs have the capacity to bind tumor antigen more avidly than endogenous T-cell receptors.

Chimeric antigen receptors usually recognize unprocessed antigens expressed on the surface of cancer cells.

89% of ALL patients unresponsive to standard treatment, to include both adult and pediatric patients experienced remission after the immunotherapy treatment.

CAR therapy involves extracting a patient’s T-cells from a blood sample, and then they are reprogramed genetically to produce surface receptors called CAR, similar to antibodies, which facilitate the T-cells to recognize tumor-specific antigens.

The CAR T-cell population is then expanded in the laboratory and infused back into patients to multiply and hone in to target cancer cells and destroy them.

The most common targeted antigen is CD19, found in most B-cell malignancies.

CAT T Cells directed against CD19 induce remissions in 68-93% of patients with acute B-lymphoblastic leukemia, in 57-71% of patients with CLL, and in 64-86% of those with non-Hodgkin’s lymphoma.

CAR-transduced natural killer cells in patients with a relapsed refractory CD 19-positive cancers undergo responses.

The chimeric molecule has a signalling domain which signals the T-cell to become activated to divide, proliferate, and kill targeted cells.

T cells can undergo major proliferation in vivo, increasing the the anti-tumor response.

CAR-T cells can proliferate to remarkable high degrees, ranging from a thousanfold to ten-thousanfold.

CAR-T cells can persist in the body for several years.

CAR T cells are produced on an individual basis, making their production complex and expensive.

CAR T cells associated with substantial toxic effects including cytokine release syndrome and neural toxicity.

Patients are at high risk for these toxicity‘s within the first two weeks after treatment.

Tocilizumab can be used to treat CAR T cell–induced severe or life-threatening cytokine release syndrome (CRS), which is a potentially life-threatening side effect of tisagenlecleucel, in patients aged 2 years or older.

All CARs have a stimulatory domain, usually CD3 zeta chain, and a costimulatory domain.

Costimulation domain is provided by either CD28 or 41BB (CD137).

In both CLL and ALL patients who had complete remissions also had CD19 protein expressing normal B-cells which are thought to be a marker of continued T-cell response.

Patients treated may experience a cytokine release syndrome which is a sign that the engineered T-cells are dividing within the patient and attacking the tumor cells.

Patient may need to be hospitalized for up to two weeks during the treatment process.

CAR T cell interaction with a specific surface molecule, which will often be a self-antigen found on normal and cancer cels.

CAR T cells circumvent major histocompatibility complex (MHC) presentation and therefore the pathways to this mechanism of immunological activation.

In patients with relapsed or refractory B-cell acute lymphoblastic leukemia treated with CD19 CAR T cells have noted complete response rates of 6 months of nearly 70%.

CAR T cells referred to as a living drug because their action directs a therapeutic molecule against a cellular target.

CAR T cells can cause resistance through selective pressure on an antigen.

Multiple studies have demonstrated positive results for chimeric antigen receptor (CAR) T-cells in treating relapsed and refractory multiple myeloma.

In refractory or relapsed multiple myeloma patients CAR-T-cell therapy objective response rate 50-905.

The CAR T-cells that have shown the most therapeutic promise are those targeting the CD19 protein, and the BCMA protein in multiple myeloma.

High rates of durable complete responses are reported with ciltacabtagene autoleucel in patients with relapsed or refractory multiple myeloma: phase 2 CARTITUDE-2 study.

Has a greater than 70% response rate in refractory CLL.

Between 25-35% of patients with CLL achieve a complete remission.

When effective in CLL it can induce deep remissions.

CAR-T cell therapy is a one time treatment and repeated doses are not required

This cytokine release syndrome includes : flu-like symptoms: nausea, high fever, muscle pain, shortness of breath, and low blood pressure, and symptoms can be partially controlled with an immunosuppressant drug, such as tocilizumab, which dampens the inflammatory cytokine, IL-6.

Cytokine release syndrome can evolve into a capillary leak syndrome with pulmonary edema and hypoxia, as well as severe hypotension.

CAR T cell therapy severe to life threatening cases of cytokine release syndrome has occurred in almost half of the patients treated.

Cytokine release syndrome reflects rapid T cell proliferation and immune stimulation.

Most patients who respond to therapy develop some degree of cytokine release syndrome, varying from mild to severe.

Adverse may occur for up to 3 weeks post infusion.

Adverse effects can include lethal T cell cross reactivity and cerebral edema.

Neurologic toxicity can lead to confusion, delirium, aphasia, seizures,cerebral edema and death.

Neurologic toxicity not apparently related to IL-6.

Neurologic toxicity can develop during cytokine release syndrome or after it resolves.

Neurologic toxicity does not rapidly respond to tocilizumab or anticytokine therapy.

In most cases of neurologic toxicity it resolves spontaneously with supportive care after a few days or up to a couple of weeks.

CAR T-cell therapy carries the risk of severe adverse effects such as neurotoxicity, which can result in headache, confusion, and delirium.

Among the most prevalent symptoms associated with CAR T-cell therapy is encephalopathy, a brain disease that causes confusion, with added symptoms of headache, tremor, weakness, and language dysfunction.

Many of these effects were reversible and symptoms almost always resolved over time.

These neurological deficits associated with CAR T-cell therapy originated from areas that appeared to be metabolically silent, implying that clinical assessment of neurotoxicity and the use of imaging are important.

The use of corticosteroids in neurologic toxicity is uncertain.

Patients that receive CAR Tcell CD19 therapy have their normal B cell population depleted and require immunoglobulin therapy.

Approved CAT-T cell treatments tisagenlecleucel, and axicabtagene ciloleucel.

 

Lisocabtagene maraleucel approved for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to, or who have relapsed after, at least 2 other types of systemic treatment.

CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma.

High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma, but only 50% of patients are cured.

The study investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT.

Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement.

Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3.

Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence but not peak CAR T-cell expansion.

The 2-year progression-free survival (PFS) was 30%.

With CAR-T therapy for DLBCL refractory and recurrent disease objective response rates are 74% with a complete response rate of 54%, and ongoing response of 36% and median duration has not been reached in the ZUMA-1 trial (Acicabtagene): ZUMA-5 Acicabtageneshowed high rates adorable responses in patients with a relapse or refractory indolent non-Hodgkin’s lymphoma.

Patients who have CAR T cell therapy often have hematologic toxicity such as cytopenias which impair the ability for patients to tolerate additional therapy.

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