CAR T-Cell Therapy: A Healthcare Professional’s Guide – Cancer Targets

The very first investigational oncology gene therapy known as a chimeric antigen receptor (CAR) T-cell therapy is now FDA approval. These agents — by all means an bioengineering miracle — are constructed from the patient’s own T lymphocytes to escalate their cancer-killing capability, and then re-infused back into the patient. The re-engineered T cells are then directed to kill the cancer cells.

On August 30, two thousand seventeen the FDA approved Kymriah (tisagenlecleucel), from Novartis, for certain pediatric and youthfull adult patients with a form of acute lymphoblastic leukemia (ALL).

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 bod. CAR-T can help to re-invigorate the T cell to do its job.

The rates of accomplish response with CAR T in certain leukemias and lymphomas have been epic, and some patients have been in sustained or partial remissions for years. But it’s significant to note many studies are still under FDA review for other uses and side effects can be serious.

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. The FDA has received a CAR T agent biological license application (BLA) for axicabtagene ciloleucel (KTE-C19 or Axi-Cel) from Kite Pharma. It is up for FDA review in three subtypes of aggressive B-cell non-Hodgkin lymphoma. A decision is expected in the fall of 2017. Promising results for Axi-Cel have been demonstrated in:

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 begin 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.

The subtypes of aggressive non-Hodgkin lymphoma submitted in the pivotal trial for axicabtagene ciloleucel (KTE-C19) are:

• Diffuse large B-cell lymphoma (DLBCL) – this is the most common NHL subtype, making up about thirty 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 2nd most common form of lymphoma in the US, and originally may be slow-growing (indolent). However, the risk for transformation to aggressive lymphoma (usually DLBCL) is harshly 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. Toughly two 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 (KTE-C19) is the very first CAR T-cell therapy submitted for FDA approval in the US for non-Hodgkin’s lymphoma. The pivotal, multicenter trial submitted by the manufacturer 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 one hundred one 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 six months was 41%, with 36% of patients still in finish 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 probe) had a median OS of 6.6 months.

Relapsed/Refractory Acute Lymphoblastic Leukemia

Kite’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 one studies of r/r ALL with Phase two studies embarking 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 crimson 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 amazing results in these difficult-to-treat patients. In the Phase one ZUMA-3 and ZUMA-4 trials from Kite Pharma, preliminary analysis found nine of eleven patients, or 82%, acheived a accomplish remission or a finish 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 toughly 6% of non-Hodgkin lymphomas. Treatment originally involves several standard regimens including rituximab (Rituxan). The targeted drug regimen ibrutinib (Imbruvica), a Bruton tyrosine kinase (BTK) inhibitor, was approved in two thousand thirteen 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 two ongoing single arm, open-label, multicenter ZUMA-2 examine from Kite Pharma, investigators will enroll seventy 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 probe is to assess safety and efficacy of axicabtagene ciloleucel (KTE-C19) by evaluating overall response rate (ORR) defined as partial remission plus finish 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 broad range of B-cell malignancies. Other ZUMA studies utilizing the engineered axicabtagene ciloleucel (KTE-C19) regimen include:

• ZUMA-5: Indolent (slow-growing) NHL, with very first patient enrollment expected in the very first quarter of 2017
• ZUMA-7: 2nd line DLBCL, with very first patient enrollment expected in 2017
• ZUMA-8: Chronic lymphocytic leukemia (CLL), with very first patient enrollment expected in 2017

Solid Tumor Research: Progress to Be Made

While CAR T-cell therapy in hematologic cancers is extraordinaire, 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. Fresh 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 react 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 shove on. As reported by Yong, et al in January 2017, over fifty one 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.

Related movie: