which solid tumor will be the 1st approved treatment by CART?

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Currently, CAR-T therapy is the "super star" in cancer therapy area. Two CAR-T products were approved from FDA in last two months. however, they are all targets for hematologic malignancies (blood tumor).For solid tumor, lots of works are going on, but it is more complicated because of the tumor microenvironment and so on. Right now, the most frequent targets on solid tumor are mesothhelin and GPC3. According to the data from clinical trial, more than 100 patients with solid tumor, only 3 CRs treated with CAR-T cell therapy were noticed from pediatric GD2- glioblastoma trial. so which solid tumor do you thnik will be the 1st aprroved treatment by CAR-T?

Qiuying Bao
78 months ago

3 answers

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Recent FDA approvals Kymriah (tisagenlecleucel) and Yescarta (axicabtagene ciloleucel) now make CAR T-cell treatment an option for blood cancers, 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, 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 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.
Over 50 CAR T trials are ongoing or planned for solid tumors, many of these studies are still in the early phase, include: (1) Neuroblastoma, metastatic melanoma and osteosarcoma directed against tumor antigen GD2; (2) Lung cancer, colorectal cancer, ovarian cancer, and pancreatic cancer directed against tumor antigen EGFR; (3) Glioblastoma targeting IL-13Rα2 or EGFRvIII; (4) Breast cancer, ovarian cancer, lung cancer, pancreatic cancer, and advanced sarcoma directed against tumor antigen HER2; and (5) Hepatocellular cancer, squamous cell carcinoma of the lung directed against tumor antigen GPC3.
At the end of 2016, NEJM reported a case of solid tumors specific CAR T treatment—CAR-T therapy got breakthrough in solid tumor treatment for the first time. The study was conducted by City of Hope, and the researchers used 16 CAR-T (6 surgical lesions and 10 ventricles) for IL13Rα2 antigen on a 50-year-old brain tumor (glioblastoma) patient, whose tumor reappeared 6 after surgery, chemotherapy and radiotherapy before. After this treatment, his intracranial and spinal cord tumors disappeared, and the response continued for 7.5 months, while central cytokines and immune cells increased. This dose (1 million CAR-T cells) did not have 3 level or more toxic side effects. Although this case report made us very excited, but it cannot completely solve the problem of solid tumors. Anyway, it really proved to us the CAR-T treatment effect for glioblastoma. At the 2017 AACR meeting, the same research team at the City of Hope National Cancer Center, in Duarte, California, presented exciting evidence that CAR T cells can now be made to work against solid tumors, including glioblastoma and prostate cancer. This exciting clinical trial is ongoing at the City of Hope, which has treated 22 patients so far.
In sum, the results of pilot clinical trials of CAR-T treatment on solid cancers are below expectation. Several obstacles have remained to be overcome for a successful application of CAR-T cells in solid tumor, including the lack of ideal TAAs, inefficient trafficking of CAR-T cells to tumor sites, hostile solid tumor microenvironment, and the risk of developing on-target/off-tumor toxicities. Further exploration is needed to improve the feasibility, safety, and efficiency of CAR-T therapy in solid tumors, but I would like to guess that glioblastoma will be the 1st approved treatment by CAR-T cells.
Resources:
Anderson L. CAR T-Cell Therapy: A Healthcare Professional's Guide - The Solid Tumor. Available at https://www.drugs.com/slideshow/car-t-cell-therapy-a-healthcare-professional-s-guide-the-solid-tumor-1285
Yu S, et al. Chimeric antigen receptor T cells: a novel therapy for solid tumors. Journal of Hematology & Oncology 201710:78. https://doi.org/10.1186/s13045-017-0444-9
Revelation! CAR-T Has Its “Eyes” on Solid Tumor and the Treatment of That Would Be Possible. Available at http://www.creative-biolabs.com/blog/index.php/revelation-car-t-has-its-eyes-on-solid-tumor-and-the-treatment-of-that-would-be-possible/
Tumor-targeting CAR T cell immunotherapy finally works in solid tumors; soon to be in trials for prostate cancer: At the 2017 AACR Meeting, progress was reported on the development of CAR T cell immunotherapy for treating glioblastoma and prostate cancer. Available at https://www.pcf.org/news/tumor-targeting-car-t-cell-immunotherapy-finally-works-in-solid-tumors-soon-to-be-in-trials-for-prostate-cancer/

Weihong Lai, MD, PhD, MMCi
78 months ago
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A a promising finding for the immunotherapy field, is the work of the group of Prof. Priceman, mentioned above in the post of Dr Lai.
Dr. Priceman and colleagues are also developing CAR T cells to target prostate cancer, a project that is funded by the Prostate Cancer Foundation (PCF). The team has designed a CAR molecule that targets prostate stem cell antigen (PSCA), which is expressed in ~60% of primary prostate cancers and 80-100% of metastatic prostate cancers. PSCA is also expressed by other cancers, including pancreas and bladder, meaning that PSCA-CAR T cells may have applicability beyond prostate cancer.

Pietro Carotenuto
78 months ago
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A better understanding of the multiples barriers seen in solid tumors will drive advances in CAR engineering and in clinical trial design. For example, it is currently unclear if aggressive lymphodepletion suggested for TIL therapy will also be needed for CAR T-cell infusion. A number of groups are currently exploring this issue. In preliminary studies from our institution, the use of cyclophosphamide appears to increase blood levels of CARs after infusion, suggesting that some sort of lymphodepletion may be needed in solid tumor therapy.

Pietro Carotenuto
78 months ago

Have some input?