By David Haas
Wednesday June 5, 2019
Treatment options available to cancer patients have both improved and grown over the past decade. The development of personalized medicine has enabled patients to seek a new route, tailoring their treatments specifically to their situations. One outcome of this unique treatment approach is the development of CAR-T (chimeric antigen receptor T) cell therapy (see: Taking Personalized Medicine to a New Level: CAR-T Cell Therapy).
T cells are extremely efficient at recognizing and eliminating abnormal or non-self tissues, whether that be virally infected, or tumor cells. In recent years, CAR-T cells have been engineered as a therapeutic product, specifically developed for an individuals’ particular tumor. This has proven to be a very effective way of treating certain types of hematologic malignancies, and now studies are being conducted to understand how this treatment can impact difficult-to-treat solid tumor cancers such as malignant pleural mesothelioma (MPM).
Malignant Pleural Mesothelioma
MPM predominantly develops within the pleura and makes up the majority of mesothelioma cases.1 Traditional treatment such as chemotherapy and radiation are mostly ineffective in increasing survival rate. Roughly 9 percent of those diagnosed with MPM will live past five years post-treatment. Chemotherapy with pemetrexed and cisplatin, are often administered as the first-line of treatment for patients with MPM who are deemed suitable for this regimen. While chemotherapy can suppress symptoms, the median overall survival of those treated is approximately 14 to 25 months.2 This is why the development of novel treatments for this specific type of mesothelioma is so important. Solid tumor cancers often do not respond well to traditional drug delivery interventions, but alternative drug targets could prove more effective in such hard-to-treat malignancies.
All T cells carry a T-cell receptor (TCR), which is specialized for a specific antigen target generally expressed on the cell surface. CAR-T cells are engineered with TCRs specific for a tumor antigen, expressed only on cancer cells, but not normal cells. This way, CAR-T cells are generated for the tumor antigen killing off only the cancer, and in the hope of not causing a lot of collateral damage.
Mesothelin, a tumor differentiation antigen, is a prime target for T-cell therapy, as these antigens are expressed at lower levels on normal tissues while being oftentimes overexpressed on MPM cancer cells. Recently, researchers at the Perelman School of Medicine at the University of Pennsylvania conducted studies examining the effects of T-cell therapy on MPM. An initial phase I trial engineered T cells transiently expressing CARS composed of an extracellular mesothelin antigen receptor coupled with intracellular 4-1BB and CD3 signaling domains.3
The 4-1BB and CD3 signaling domains were included in an effort to strike a balance between antitumor activity and off-target cytotoxicity.
In this phase I study, seven patients with mesothelioma and seven with pancreatic cancer were enrolled. No patients in this trial showed evidence of on-target, off-tumor toxicity, which is a promising first sign, and two of the patients in this study actually demonstrated evidence of tumor shrinkage.4 While this was not consistent among all patients, it indicates that this treatment could be a viable option for a certain subset of patients. As research and development efforts progress, experts may be able to accurately identify patients who can benefit from this therapy.
Researchers at the Memorial Sloan Kettering Cancer Center (MSK) have also been conducting research on MPM T-cell responses. Of the 12 patients who participated in their recent study, 10 suffer from MPM. All of the patients were given a single dose of IcasM28z CAR T-cells intrapleurally and showed no signs of on-target, off-tumor or therapy-related toxicity.5 IcasM28z contain Icaspase-9, which acts as a safety measure within these T cells. If there is a heightened presence of toxicity due to T-cell infusion, medication can be intravenously administered that will interact with Icaspase-9 and kill all CAR-T cells.6 Similar to the previous study that was discussed, five of the study participants showed evidence of tumor regression, with one patient remaining clinically well eight months post T-cell infusion. While this is promising research, the number of patients in each of these studies remains frustratingly small.
One of the only T-cell therapies currently on the market is Novartis’ therapy known as Kymriah. This form of one-time treatment has a list price of $475,000, making it a very exclusive and expensive option for those who are suffering from certain blood cancers.7 While the price of this treatment is very high, it is somewhat justified by its efficacy and the lack of competitive drug options.
With more data on how CAR-T cell therapy works, along with wider applications of this technology and improvements in manufacturing processes, it’s plausible that pricing will become more affordable in the near future and additional patients will be able to benefit from these clinical trials. This new approach to harnessing immunology to fight treatment-resistant cancers could have a significant impact on devastating diseases like MPM in years to come.
1. https://www.mesothelioma.com/mesothelioma/types/pleural.htm. Accessed 03/24/19.
2. Cinausero M, Rihawi K, et al. Chemotherapy treatment in malignant pleural mesothelioma: a difficult history. National Center for Biotechnology Information. 2018 Jan; 10(Suppl 2): S304–S310. doi: 10.21037/jtd.2017.10.19
3. & 4. Beatty G.L., Haas A.R., et al. Mesothelin-specific chimeric antigen receptor mRNA-engineered T cells induce anti-tumor activity in solid malignancies. National Center for Biotechnology Information. 2014 Feb;2(2):112-20. DOI: 10.1158/2326-6066.CIR-13-0170
5. American Association for Cancer Research. (2019). Mesothelin-targeted CAR T-cell therapy shows early promise in patients with solid tumors [press release]. Retrieved from https://www.sciencedaily.com/releases/2019/03/190331192535.htm.
6. Gargett T, Brown M. The inducible caspase-9 suicide gene system as a “safety switch” to limit on-target, off-tumor toxicities of chimeric antigen receptor T cells. National Center for Biotechnology Information. 2014; 5: 235. DOI: 10.3389/fphar.2014.00235.
7. Lopes G, Nahas G.R. Chimeric antigen receptor T cells, a savior with a high price. National Center for Biotechnology Information. 2018 Apr;7(2):21. DOI: 10.21037/cco.2018.04.02.
David Haas is a health investigator who is immersed in understanding the development of breakthrough immunotherapy treatments. He spends his time writing on these therapies and consulting with researchers about the latest progress towards finding a cure for cancer.
Reviewed for accuracy by Dr. Katy Moncivais – Dr. Moncivais holds a Ph.D. in Biomedical Engineering from The University of Texas at Austin. She actively works and studies in the field of regenerative medicine and is a consultant on a variety of topics pertaining to cell culture.