CAR T-Cell Therapy: A Healthcare Professional's Guide - The Top 10 Questions Answered
What is CAR T-Cell Therapy?
Chimeric antigen receptor (CAR) T-cell therapy is a new form of cancer treatment now FDA approved. This personalized therapy is engineered from a patient's own T-lymphocytes to actively search and destroy cancer cells in patients failing other options. Several pharmaceuticals companies have CAR T-cells under investigation. Recently, the FDA Advisory Committee gave their stamp of approval on this marvel of biomedical engineering, and final decisions are expected in the fall, and Kymriah (tisagenlecleucel) from Novartis is now approved for some pediatric and young adult patients with acute lymphoblastic leukemia (ALL).
CAR T-cell therapy is not a "drug" in the usual sense, as might be used in chemotherapy; instead, it is a living biologic created from a patient's own cells. T-cells normally target cancer cells, but aren't always as efficient as they should be, and the rebuilt CAR T-cells can help to boost their cancer-killing ability.
What is CAR T cell therapy?
- In CAR T, a patient's T-cells (white blood cells) are separated out and constructed to express a chimeric antigen receptor (CAR) to target the tumor antigen. A CAR is a protein attached to the T-cell surface.
- The tumor antigen, such as CD19, is a protein on the surface of agressive B-cell lymphomas and leukemias. Different cancers have different antigens, and CAR T is specific for certain antigens.
- The reengineered CAR T-cell is then infused back into the patient to find the specific cancer antigen and deal a lethal blow.
- It's been highly successful in treatment, with durable complete responses ongoing for more than 3 years in some trials, but side effects can be difficult in the short-run.
More more information on CAR T-cell action, see these related slideshows:
What Kind of Cancer Does CAR T-Cell Therapy Treat?
To date, the main successes seen with CAR T are with advanced hematologic malignancies such as B-cell non-Hodgkin lymphomas (NHL) and leukemias. The CD19 antigen has been the most common tumor target for these cancers.
- Aggressive B-cell non-Hodgkin lymphoma (diffuse large b-cell lymphoma, primary mediastinal b-cell lymphoma, and transformed follicular lymphoma) (pivotal ZUMA-1 trial)
- Relapsed/Refractory Mantle Cell Lymphoma
- Chronic Lymphocytic Leukemia
- Adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia
Studies are also in process looking at CAR T cell therapy in solid tumors, such as gliobastomas, pancreatic and ovarian cancers, although more challenges exist with solid tumor treatment.
Is CAR T-Cell Therapy Approved?
At a July 2017 FDA Oncology Advisory Committee meeting, the panel reviewed Novartis’ CTL019 (tisagenlecleucel), an agent for aggressive pediatric and young adult acute B-cell acute lymphoblastic leukemia (ALL). The committee unanimously recommended its approval. On August 30, 2017, the FDA approved Kymriah (tisagenlecleucel), the first U.S. CAR-T cell therapy.
The second available CAR T agent, Kite/Gilead's Yescarta (axicabtagene ciloleucel), also previously known as KTE-C19, was approved on October 18, 2017.
Specifically, Yescarta was approved in adult patients with large B-cell lymphoma after at least two other kinds of treatment failed. Lymphoma types include diffuse large B-cell lymphoma (DLBCL), primary mediastinal large B-cell lymphoma, high grade B-cell lymphoma and DLBCL arising from follicular lymphoma. Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma. Of note, Kite Pharma, the original developer of KTE-C19, was bought by Gilead Pharmaceuticals in late August 2017 for close to $12 billion.
How Is CAR T Cell Therapy Given?
CAR T-cell therapy is a biologic-type of living drug which involves a personalized procedure, unlike taking a daily pill or receiving several rounds of chemotherapy. The receipt of CAR T cell therapy is a one-time procedure, and the CAR-T cells may continue to replicate to fight the cancer in the body. But side effects can be challenging and serious.
Here's the general process:
- Apheresis, a procedure to collect the patient's white blood cells (lymphocytes) is performed in the hospital. Then the T-cells are isolated.
- The T-cells are sent to lab where they are genetically engineered to construct a chimeric antigen receptor (CAR) on the cell surface. Genes are inserted into the T-cells using an inactive virus which allows the CAR T-cell to activate, recognize, and kill the cancer cell.
- The CAR T-cell is grown in the lab for roughly 2 weeks to greatly multiply the dose. The cells are frozen and then sent to the hospital for re-infusion to the patient.
- In the mean time, the patient has received conditioning chemotherapy to help lower the white blood cell count and allow the CAR T-cells to be better accepted.
What Are the Side Effects With CAR T-Cell Therapy?
CAR T-cell therapy is used in patients with high tumor burden and advanced disease; these patients have run out of treatment options. However, side effects of CAR T-cell therapy can be daunting. Ironically, some of the adverse events are due to cytokine release that occurs because the patient is having a positive response to therapy. Nonetheless, clinicians are researching how to tame CAR T-cell therapy side effects to lessen the impact on the patient.
The most commonly reported adverse effects seen in CAR T-cell therapy clinical trials include:
- Cytokine Release Syndrome (CRS): Very high fevers, sharp drops in blood pressure, tachycardia, and low oxygenation can occur, usually in the first week. Administration of tocilizumab (Actmera), an agent that blocks IL-6, has been used to manage cases of CRS.
- Neurotoxicity: May include delirium, confusion, somnolence, agitation, delirium, ataxia, aphasia, and seizure.
- B-Cell Aplasia: B cell aplasia is defined as low or absent B cells (a type of white blood cell) and is an expected side effect of CAR T cell therapy that can boost infection risk; monthly intravenous immunoglobulin (Ig) infusions help manage this side effect.
- Tumor-Lysis Syndrome (TLS): Another expected side effect; TLS occurs due to cell death and subsequent release of contents into the bloodstream; metabolic, electrolyte and possible organ failure complications ensue; management is standard supportive therapy.
- Cerebral Edema: Can be fatal; at least eight cerebral edema-related deaths have been reported.
Studies for CAR T Cell Therapy
While side effects can be challenging, the fact remains that complete and partial remissions are impressive with CAR T-cell therapy. All eligible patients have exhausted their cancer treatment options, and CAR T-cell therapy may be their last hope to extend survival.
Yescarta (axicabtagene ciloleucel) from Gilead is an anti-CD19 CAR-T therapy directed against aggressive B-cell cancers and under study for various relapsed and refractory hematologic malignancies, including:
- Aggressive B-cell Non-Hodgkin Lymphoma (diffuse large b-cell lymphoma, primary mediastinal b-cell lymphoma, and transformed follicular lymphoma) (ZUMA-1 trial) - pivotal clincial trial submitted to the FDA for the October 2017 approval of Yescarta.
- Relapsed/Refractory Mantle Cell Lymphoma (ZUMA-2 trial)
- Adult and Pediatric Relapsed/Refractory Acute Lymphoblastic Leukemia (ZUMA-3 and ZUMA-4 trials)
- Indolent B-Cell Non-Hodgkin Lymphoma (ZUMA-5)
- Use With Atezolizumab (Tecentriq), an anti-PD-L1 checkpoint inhibitor, in patients with refractory diffuse large B-cell lymphoma (DLBCL) (ZUMA-6) - inhibiting PD-L1 with atezolizumab may enhance and prolong the activity and proliferation of axicabtagene ciloleucel.
- Chronic Lymphocytic Leukemia (ZUMA-8 trial)
What's Next for CAR T-Cell Therapy?
Top issues for researchers and clinicians utilizing CAR T-cell therapy include:
- Shortening the manufacturing time and vein-to-vein time, scaling productivity, managing side effects, and improving patient outcomes.
- Expanding the patient population to be able to treat larger populations in need of CAR T.
- Extending treatment on a more local or regional hospital level, instead of at distant or out-of-state academic research centers.
- Educating healthcare providers and patients on this novel and complicated cancer treatment.
- In addition to CD19, defining additional tumor antigens for CAR T-cell receptors.
In fact, new CAR T cell tumor antigens are already under research. In August 2017, Kite Pharma announced the submission of an Investigational New Drug (IND) application to initiate a Phase 1 trial of KITE-585, a CAR-T cell therapy engineered to target B-cell maturation antigen (BCMA) in patients with relapsed or refractory multiple myeloma. Multiple myeloma is a blood cancer formed by plasma cells in bone marrow and is predicted to cause over 12,000 deaths in 2017.
BCMA is expressed on the surface of malignant plasma cells in most patients with multiple myeloma, and is also found on normal plasma cells and certain mature B-cell lineage cells but is absent from other tissues. KITE-585 contains a receptor derived from a fully human monoclonal antibody and a CD28 costimulatory domain intended for optimized T-cell expansion and function. In preclinical studies, KITE-585 demonstrated activity across a range of low and high BCMA expressing targets.
Does CAR T Cell Therapy Work in Solid Tumors?
CAR T cell therapy has shown great success in clinical trials with blood cancers. However, most cancers seen in clinic are of the solid type, such as lung cancer, breast cancer, or colon cancer. Utilizing CAR T-cell therapy to treat solid tumors is actively under research but studies have not demonstrated the success seen with blood cancers, possibly due to:
- An inhospitable solid tumor microenvironment (oxidative stress, lack of nutrients, an acidic pH).
- Heterogenous antigens.
- The presence of immunosuppresive pathways like immune checkpoint.
T-cell receptor (TCR) therapy is a new option with ongoing research to target a wide range of solid tumors. Like CAR T-cell therapy, TCR therapy yields tumor apoptosis and programmed cell death, can expand T-cells numbers, and results in circulation throughout the body to target distant cancer cells.
In January 2017, Kite Pharma submitted an investigational new drug (IND) application with the FDA to initiate trials with KITE-718, their first T-cell therapy engineered to express T-cell receptors. KITE-718 T-cell receptors target the MAGE A3/A6 antigen found on a broad range of solid tumors, such as bladder cancer, esophageal cancer, head and neck cancer, lung cancer and ovarian cancer.
How Much Does CAR T-Cell Therapy Cost?
A personalized and complicated engineering process such as CAR T cell development is expected to be costly. Kymriah, the first CAR-T cell therapy approval, will be marketed at $475,000 per treatment, much less than analysts orginally thought. The cost of Kite/Gilead's Yescarta is even less: $373,000 per treatment regimen.
What factors push up the cost of CAR T?
- Specialized facilities and healthcare providers
- Manufacturing costs
- Possible need for intensive care post-infusion due to serious adverse events
- Prolonged hospitalization
Feinberg and colleagues suggest that a bundled payment approach, where a limited number of facilities offer treatment with contractual payment agreements may be one reimbursement strategy, similar to the current precedent set by allogeneic HSCT.
The commercial potential of CAR T-cell therapy could exceed $1.5 billion by 2020. An added bonus: rapid development of other novel cancer treatments stemming from the research involved with CAR T will be a benefit for all. With the approval of CAR T-cell therapy, the fight to end cancer in its tracks moves closer to the finish line.
Is There A Universal CAR-T Cell Therapy?
Creating a universal CAR T agent could help avoid the lengthy and sometimes dangerous time period from apheresis of T-cells to re-infusion, which on average runs 2 to 2.5 weeks, although these timelines are expected to get shorter.
"Off-the-shelf" or "universal" T-cell therapy (allogenic) CAR T-cell production is under research. While personalized CAR T-cell therapy developed from the patient's own T-cells is best to limit any potential graft-versus-host-disease (GVHD), some patients cannot wait for the development of their own personalized product. Some patients may be too sick to wait for production, or some cannot tolerate apheresis at all.
As reported by Kite Pharma in July 2016 and April 2017, they have partnered with UCLA investigators to advance the technology needed to develop this "off-the-shelf" technology. Research invoves an artificial thymic organoid (ATO) cell culture system that replicates the differentiation of T-cells ex vivo. It still remains to be seen if allogeneic "off-the-shelf" T-cell products will be as robust as autologous CAR T-cell therapies.
In addition, the use of natural killer (NK) cells are under study at MD Anderson Cancer Center in Houston. CAR NK cell studies are targeting both hematologic and solid tumors. Creating a bank of allogeneic NK cells could be an advantage for patients who cannot wait for the creation of personalized therapy from their own T-cells.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - The Top 10 Questions: Answered
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