CAR T-Cell Therapy: A Healthcare Professional's Guide - Cancer Targets
Gene Therapy to the Rescue
Chimeric antigen receptor (CAR) T-cell therapies are now FDA approval. These agents -- by all means an bioengineering marvel -- are constructed from the patient's own T lymphocytes and then re-infused back into the patient. The re-engineered T cells are then directed to seek out and kill the cancer cells.
On August 30, 2017 the FDA approved Kymriah (tisagenlecleucel), from Novartis, for certain pediatric and young adult patients with a form of acute lymphoblastic leukemia (ALL). In addition, on October 18, 2017 Kite Pharma/Gilead's Yescarta (axicabtagene ciloleucel) was approved to treat adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy.
Naturally occurring T cells aren't always as efficient as they should be in targeting malignancies. Cancers can evade the T-cells, the T-cells become less effective, the T-cells don't replicate appropriately, and they can miss identifying the tumor target as a foreign body. CAR-T can help to re-invigorate the T cell to do its job.
The rates of complete response with CAR T in certain leukemias and lymphomas have been impressive, and some patients have been in sustained or partial remissions for years. But it's important to note that many studies are still ongoing for other cancer types.
CAR T-Cell Therapy: Cancer Success
The primary successes seen with CAR T are with refractory hematologic malignancies such as non-Hodgkin lymphomas (NHL) and B-cell leukemias. The C19 tumor target has been the most common tumor target for these cancers. Yescarta (axicabtagene ciloleucel) was approved for 3 subtypes of aggressive B-cell Non-Hodgkin lymphoma:
- diffuse large b-cell lymphoma (DLBCL)
- primary mediastinal large b-cell lymphoma
- high grade B-cell lymphoma
- DLBCL arising from follicular lymphoma
Yescarta is not indicated for the treatment of patients with primary central nervous system lymphoma.
Other research with axicabtagene ciloleucel includes:
Other cancer types under early phase investigation include:
Learn More, Including Side Effects of CAR T:
Aggressive B Cell Non-Hodgkin Lymphomas
About 90% of lymphoma cases start in the B cells. The C19 tumor target that is sought by the CAR T cell therapy is found on the tumor surface or on B lymphocytes. Other cells are not targeted by the CAR therapy if they do not exhibit the C19 target.
Three subtypes of aggressive non-Hodgkin lymphoma approved for Yescarta (axicabtagene) ciloleucel include:
- Diffuse large B-cell lymphoma (DLBCL) - this is the most common NHL subtype, making up about 30 percent of US cases. DLBCL is aggressive with large masses of B lymphocytes and involves the liver, spleen, bone marrow or other organs. Typically, the treatment for refractory DLBCL is 3rd or 4th line chemotherapy drugs. These patients have a poor prognosis and few treatment options.
- Transformed follicular lymphoma - Follicular lymphoma is the second most common form of lymphoma in the US, and initially may be slow-growing (indolent). However, the risk for transformation to aggressive lymphoma (usually DLBCL) is roughly 30%. A genetic defect, a specific chromosomal abnormality can result in this type of aggressive lymphoma being resistant to standard treatments. Patients with transformed lymphoma who fail standard chemotherapy have a very poor prognosis.
- Mediastinal B-cell lymphoma - This is an aggressive form of DLBCL where a large mass forms in the center of the chest and can compress veins need to carry blood and oxygen to the heart. Roughly 2 to 3% of patients with NHL will have this subtype, usually women in their 30's or 40's. Chemotherapy is typically used for treatment; but radiation may also be used.
Pivotal Trial: Aggressive B-Cell Non-Hodgkin Lymphoma
[Axicabtagene ciloleucel] (Yescarta) was the first CAR T-cell therapy approved for non-Hodgkin's lymphoma in the U.S. The multicenter trial submitted to the FDA by Kite Pharma recruited patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (NHL) who were also ineligible for autologous stem cell transplant.
In this pivotal trial known as ZUMA-1, researchers assessed treatment of aggressive refractory B-cell lymphoma with axicabtagene ciloleucel in 101 patients with three subsets of refractory NHL. Here are the major results:
- Objective response rate (ORR) of 82%, the primary endpoint, was met
- ORR at 6 months was 41%, with 36% of patients still in complete response (CR)
- At 8.7 months, the median overall survival was not yet reached, but a meta-analysis of a similar population receiving recommended approved treatments for refractory NHL (SCHOLAR-1 study) had a median OS of 6.6 months.
Relapsed/Refractory Acute Lymphoblastic Leukemia
Kite Pharma's CAR T-cell therapy is also under research for the treatment of relapsed/refractory acute lymphoblastic leukemia (r/r ALL) in pediatric and adults patients. Axicabtagene ciloleucel (KTE-C19) is in late-stage Phase 1 studies of r/r ALL with Phase 2 studies starting in 2017.
ALL is a cancer of the blood and bone marrow that results in proliferation of immature lymphocytes that are ineffective in fighting infections. In addition, healthy red blood cells from the bone marrow cannot be formed, leading to anemia. There are several approaches to treatment of ALL:
- Blood transfusions
- Chemotherapy, targeted cancer therapy
- Radiation treatment
- Stem cell transplant
Despite these effective treatments, some patients will still relapse over time or be refractory to standard therapy. Investigational CAR T cell therapy has shown impressive results in these difficult-to-treat patients. In the Phase 1 ZUMA-3 and ZUMA-4 trials from Kite Pharma, preliminary analysis found 9 of 11 patients, or 82%, acheived a complete remission or a complete remission with incomplete or partial blood count recovery. In addition, all patients tested negative for minimal residual disease (MRD), which correlates with ALL disease relapse.
Relapsed/Refractory Mantle Cell Lymphoma
Relapsed or refractory mantle cell lymphoma (r/r MCL) is an uncommon, aggressive and often incurable B cell cancer that makes up roughly 6% of non-Hodgkin lymphomas. Treatment initially involves several standard regimens including rituximab (Rituxan). The targeted drug regimen ibrutinib (Imbruvica), a Bruton tyrosine kinase (BTK) inhibitor, was approved in 2013 for patients with relapsed MCL. Autologous stem cell transplantation may also be an option.
CAR T is under research in r/r MCL. Studies at the National Cancer Institute (NCI) have demonstrated durable remissions using CAR T-cell therapy in r/r MCL. In the Phase 2 ongoing single arm, open-label, multicenter ZUMA-2 study from Kite Pharma, investigators will enroll 70 patients with r/r MCL whose disease is refractory to or has relapsed following anthracycline- or bendamustine-containing chemotherapy and anti-CD20 monoclonal antibody therapy and ibrutinib.
The primary objective of this study is to assess safety and efficacy of axicabtagene ciloleucel by evaluating overall response rate (ORR) defined as partial remission plus complete remission. Secondary endpoints such as duration of response, progression-free survival, and overall survival are also being evaluated.
Other ZUMA Studies
CAR T-cell therapy has been found to be effective across a wide range of B-cell malignancies. Other ZUMA studies utilizing the engineered axicabtagene ciloleucel regimen include:
- ZUMA-5: Indolent (slow-growing) NHL, with first patient enrollment expected in the first quarter of 2017
- ZUMA-7: 2nd line DLBCL, with first patient enrollment expected in 2017
- ZUMA-8: Chronic lymphocytic leukemia (CLL), with first patient enrollment expected in 2017
Solid Tumor Research: Progress to Be Made
While CAR T-cell therapy in hematologic cancers is impressive, the fact remains that most deadly cancers are solid tumors like lung, breast, or colon cancer.
Efforts are ongoing to understand how CAR T-cell therapy can be utilized to treat solid tumors. New tumor targets will need to be identified. The mechanism of CAR T interactions with a solid tumor as compared to a hematologic malignancy is a priority. To date, most studies of solid tumors being treated with CAR T have failed to respond to treatment and toxicities have been serious. Solid tumors present an inhospitable microenviroment for T cells and lead to anergy (lack of an immune response) of the T cell.
However, researchers push on. As reported by Yong, et al in January 2017, over 51 CAR T trials were ongoing (primarily in Phase 1) or planned for solid tumors. CAR T studies listed for solid tumors include:
- Neuroblastoma, metastatic melanoma and osteosarcoma directed against tumor antigen GD2
- Lung, colorectal, ovary, pancreatic directed against tumor antigen EGFR
- Breast, ovarian, lung, pancreatic, advanced sarcoma directed against tumor antigen HER2
- Hepatocellular cancer, squamous cell carcinoma of the lung directed against tumor antigen GPC3
Positive results have been reported for neuroblastoma (GD2) and for sarcoma (HER2). In addition, T cell receptor (TCR) treatment is also under investigation. These engineered autologous T cells may have higher success rates in solid tumors.
To research additional enrolling clinical trials for CAR T cell therapy, visit ClinicalTrials.gov.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - Cancer Targets
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