Anti-CD19 CAR-T therapy has demonstrated potent clinical efficacy in patients with B-cell leukemia and lymphoma. However, this therapy faces many challenges in the context of solid tumors. Most proteins overexpressed on cancer cells may also be expressed on normal cells. CAR-T cells cannot distinguish cancer cells from normal cells. Five years ago, one patient died after the treatment with anti-HER2 CAR-T due to the expression of HER2 in lung tissues.
CD19 is not known to be expressed on any healthy tissue other than B cells. Even though such CAR-T cells attack cancer cells and normal B cells, patients can live without B cell for a long time. Further, CD19 is not expressed on hematopoietic stem cells, and therefore B cells should return when the CAR-T cell is no longer present. This may not be the case with solid tumors.
To make CAR-T therapy applicable to solid tumors, Dr. Laurence Cooper of ZIOPHARM Oncology (NASDAQ: ZIOP) developed CAR-T with reduced affinity, and showed that these CAR-T cells could distinguish cancer from normal cells. In other words, Cooper’s CAR-T cells could minimize the “on target off tumor” toxicity in mice.
The researchers chose wild-type EGFR as a target. The protein is overexpressed glioblastoma but is also found at low levels on certain normal cells. Two CARs were generated from cetuximab (cetux) and nimotuzumab (nimo), respectively. Cetux has higher affinity for EGFR, while nimo has low lower affinity.
The researchers then tested the anti-EGFR CAR-T cells in NSG mice with glioma. Cetux-CAR-T cells and nimo-CAR-T cells both significantly inhibited tumor growth. However, the cetux-CAR-T cells caused significant toxicity, resulting in significant death of mice within 7 days of T-cell infusion. The nimo-CAR-T cells have no apparent toxicity.
NSG mice lack mature T cells, B cells, and NK cells, and are also deficient in multiple cytokine signaling pathways. It is unclear whether CAR-T with low-affinity could reduce cytokine storm, a common life threatening side effect associated with CAR-T therapy. The researchers used cancer cells that express a median density of 240,000 molecules of EGFR/cell to establish mouse model. In patients, it should be far more complicated.
 Mol Ther. 2010, 18(4), 843-851.
 Cancer Res. 2015, doi: 10.1158/0008-5472.CAN-15-0139.