CAR T-Cell Therapy: A Healthcare Professional's Guide - The Solid Tumor
Solid Tumor Research: Ongoing
CAR T-cell therapy has shown great success in hematologic malignancies, such as non-Hodgkin's lymphoma (diffuse large B-cell lymphoma (DLBCL), follicular lymphoma), acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), and multiple myeloma. However, the reality is that most cancers seen in the clinic are solid tumors, like lung cancer, breast cancer, or colon cancer.
Utilizing CAR T-cell therapy to treat solid tumors has not been met with the success seen with blood cancers. In fact, many studies of solid tumors being treated with CAR T have failed to respond to treatment and toxicities have been serious.
Researchers are continuing to understand how CAR T-cell therapy, or other engineered T-cell options, can be more safely and effectively used to treat solid tumors. Areas under research include:
- Finding new tumor-associated antigens (TAAs) not found on healthy tissue.
- Continuing to research the inhospitable solid tumor micro-environment.
- Learning how the endogenous and engineered T-cell interacts with the solid tumor.
- Ongoing research into T-cell receptor (TCR) therapy.
What Tumors Are Under Study?
Yong and colleagues reported in 2017 that over 50 CAR T trials were ongoing or planned for solid tumors. Many of these studies are still in the early phase.
A few CAR T studies listed for solid tumors and associated antigens include:
- Neuroblastoma, metastatic melanoma and osteosarcoma directed against tumor antigen GD2
- Lung cancer, colorectal cancer, ovarian cancer, and pancreatic cancer directed against tumor antigen EGFR
- Glioblastoma targeting IL-13Rα2 or EGFRvIII
- Breast cancer, ovarian cancer, lung cancer, pancreatic cancer, and advanced sarcoma directed against tumor antigen HER2
- Hepatocellular cancer, squamous cell carcinoma of the lung directed against tumor antigen GPC3
And coming down the pike? T-cell receptor (TCR) therapy, another exciting investigational type of engineered immunotherapy, may demonstrate even higher success rates for solid tumors.
The Challenging Solid Tumor Microenvironment
The challenging tumor microenvironment is another obstacle with CAR T-cell therapy of solid tumors.
As reported by Newick and colleagues, significant hurdles include:
- Trafficking: CAR T cells must successfully reach the solid tumor, infiltrate the stroma, and overcome mismatched chemotactic signals.
- A tumor environment marked by oxidative stress, lack of nutrients, an acidic pH, and low oxygen levels.
- Target antigens that are heterogenous, often within primary and metastatic tumors; unlike blood cancers which have homogenous antigens.
- Escaping infiltrating, tumor-protective immune cells like regulatory T cells (Tregs) or tumor-associated macrophages.
- Overcoming the immunosuppresive pathways that inhibit CAR activity, such as the immune checkpoint.
Due to poor trafficking after intravenous infusion of CAR T-cell therapy, local instillation directly into the tumor area is under research, but this technique may lead to challenges with distribution of CAR T cells to distant malignant sites.
CAR-T's and Solid Tumors: On Target-Off Tumor Toxicity
CAR T success in hematologic malignancies like lymphoma is partly due to the fact that the CD19 tumor antigen is not present on other cells -- except B cells. This helps to spare healthy tissues that do not express this antigen. However, B cell aplasia can occur, a type of "on target-off tumor" toxicity, where the CAR T-cells destroy normal B cells, yielding an increased risk of infection. In studies, B cell aplasia due to CAR T cell therapy is managed with monthly intravenous immunoglobulin (Ig) infusions.
With a solid tumor, target antigens are not as specific as with blood cancers. Researchers are trying to pinpoint ways to prevent "on target-off tumor" toxicity with CAR T cell therapy directed towards solid tumors. In one case report from Morgan and colleagues, a fatality occurred after infusion with a high affinity HER2-CAR, as healthy tissues with these targets were rapidly attacked in the lung, leading to cytokine storm, and eventual death due to respiratory and cardiac distress.
What methods are researchers looking at to prevent "on target-off tumor" toxicity?
- Thorough preclinical toxicology studies to identify agents with a high chance of this toxicity.
- Lower and slower dose escalation studies.
- Insertion of suicide genes which can be activated in response to adverse events.
- Engineering the CAR so that it must recognize two antigens for activation.
T-Cell Receptor Therapy: The Next Generation
T cells are one type of lymphocyte important for the immune system to function properly. As with CAR T-cell therapy effect on hematologic cancers, T-cell receptor (TCR) therapy is an immuno-oncology engineering feat with ongoing research to target a wide range of solid tumors.
For example, research is ongoing with cancer-specific proteins not expressed in normal, healthy cells, such as:
- Cancer testis antigens
- Viral antigens
TCRs are proteins that allow T cells to "see" cancer targets on the cancer cell surface or inside the cancer cell. TCRs that are specific to a cancer can be isolated from the body and undergo a process to yield many engineered T cells that recognize and attack various types of solid and blood cancers. 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.
KITE-718: A T-Cell Receptor Therapy
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. This trial, currently in Phase I, is designed to assess the safety and efficacy of KITE-718 on a broad range of solid tumors. Of note, Kite Pharma was acquired by Gilead Pharmaceuticals in August 2017.
KITE-718 T-cell receptors target MAGE A3/A6 antigen, commonly found in cancers such as:
MAGE A3 and MAGE A6 fragments are bound to Class II human leukocyte antigen (HLA) (DPB1 04:01), found in 50 to 70 percent of Caucasians.
Original work with MAGE A3/A6 was done by the National Cancer Institute where tumor regression was demonstrated in multiple different types of tumors and no off target toxicity was reported.
KITE-439: HPV Cancers
Human papillomavirus (HPV) is often thought of with cervical cancer, but it is also the foundation for many head and neck and anogenital cancers. HPV causes over 30,000 cancers per year in the U.S., with over 11,000 deaths.
According to the Centers for Disease Control and Prevention (CDC), cervical cancer is the most common HPV-associated cancer among women, and oropharyngeal cancers are the most common among men. HPV-16 is the most common strain found in these cancers.
KITE-439 is an investigational T-cell receptor (TCR) therapy in pre-IND phase and directed against HPV-16 E6 and E7 antigens for the treatment of HPV-linked cancers. Kite Pharma/Gilead and the National Cancer Institute are also collaborating on HPV cancer research. This novel TCR therapy is being evaluated as monotherapy and in combination with a checkpoint inhibitor in HPV-16 associated solid tumors, like cervical and head and neck cancers.
Finished: CAR T-Cell Therapy: A Healthcare Professional's Guide - The Solid Tumor
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Kite Pharma Expands Development of T-Cell Receptor (TCR) Therapies Targeting HPV-Associated Cancers in Partnership with the National Cancer Institute (NCI). Press Release. June 20, 2016. Accessed June 22, 2017 http://ir.kitepharma.com/releasedetail.cfm?releaseid=976295
Kite Pharma Submits Investigational New Drug (IND) Application for KITE-718, an Investigational Next Generation T-Cell Receptor (TCR) Therapy Targeting Cancer Antigens MAGE A3 and MAGE A6. Press Release. Jan 3, 2017. Accessed June 22, 2017 at http://ir.kitepharma.com/releasedetail.cfm?releaseid=1005990