Investigators report Phase I results of CAR-T therapy in solid tumors

Investigators of the University of Pennsylvania report Phase I results of CAR-T therapy in solid tumors at AACR2015. The therapy appears safe in the patients treated so far, but the anti-tumor efficacy was not good as expected.

The CAR-T therapy, known as CART-meso, targets mesothelin, a antigen present on normal mesothelial cells and overexpressed in several tumors.

In the study, five patients with recurrent advanced solid tumors (2 ovarian, 2 epithelial mesothelioma, and 1 pancreatic) were treated with a single infusion of 1-3×10^7 CART-meso cells.

CAR-T cells were found to traffic to tumor sites as well as to off-tumor on-target sites, but no off-tumor on-target toxicities was observed. CAR-T cells were detectable in the blood stream in all patients up to Day 21-28 after infusion.

Anti-tumor efficacy was suggested by the clearing of cancer cells in the pleural fluid of one patient. There was clinical evidence of stable disease in another patient.

The results were not good as expected. In previous studies, CD19 CAR-T therapy showed a complete response rate of 90% in relapsed and refractory ALL[1,2].

The dosages in the solid tumors study were relatively lower than the dosages in the previous ALL trials. The peak levels of CART-meso in blood were about 2 orders of magnitude lower than CART19. Mesothelin is also found in normal tissue, thereby high dose of CAR-T may damage healthy tissue.

It’s not always easy to find a perfect CAR-T target like CD19. Although CD19 is also found in normal B cells and CAR-T therapy may deplete normal B cells, patients can live with B cell depletion for a prolonged period. Further, CD19 is not expressed on hematopoietic stem cells, and therefore B cells should return after the CAR-T treatment.

Aduro Biotech (NASDAQ:ADRO) is developing a mesothelin vaccine, known as CRS-207, for the treatment of pancreatic cancer and mesothelioma. In the Phase IIa trial in pancreatic cancer, CRS-207 plus GVAX demonstrated a statistically significant improvement in overall survival (6.1 vs. 3.9 months)[3]. Based on the results from the Phase IIa trial, CRS-207 was granted Breakthrough Therapy designation by the FDA.

[1] N Engl J Med. 2014, 371(16), 1507-1517.
[3] J Clin Oncol. 2015, 33(12), 1325-1333.


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