Studying cancer cell development, including signaling pathways and other types of cell-cell communications between immune cells and tumors, is critical to generating and evaluating possible treatments to halt the growth and spread of these cancer cells (Allard B et al., 2018; Day CP. et al., 2015).
To accomplish this impressive task, researchers require the best tumor model, an appropriate in vivo platform, and studies that accurately recapitulate the complex tumor microenvironment to yield translationally-relevant data.
Chimeric antigen receptor (CAR) T cell therapy represents the culmination of years of research in both immunology and oncology fields (check out this blog for more information). This type of therapy, was successful in the treatment of hematologic malignancies with response rates as high as 70-90% in some cases. It is based on exploiting the antibody-dependent MHC-independent antigen recognition paradigm by genetically engineering T cells (Day and Bretjens, 2016). Through manipulation, the engineered T cells specifically target and kill tumor cells (Posey, Jr., et al., 2016). The efficacy of these cells has been observed in leukemia where non-solid tumor cells, circulating within the lymphatic system, have a higher likelihood of encountering CAR T cells, inducing their killing ability (Wang et al., 2017). This therapy is rapidly moving from bench to bedside as the technology to deliver CARs to T cells quickly improves.
New studies are continually pushing the boundary of CAR T capabilities to treat TNBC, the most deadly kinds of breast cancer; they have the highest rates of metastasis, worst prognosis, and no targeted treatments (Park SH. et al., 2019). In a recently published study by Zhou and colleagues used NSG™ mice from JAX to test CAR T therapy in TNBCtumor (Zhou et al., 2019).
In a recent study by Zhou and colleagues, the authors examined the impact of a modified CAR T therapy on NSG™ mice from JAX, injected with a TNBC tumor cell line in one mammary fat pad. Using a human CAR that utilized the scFv motif from the monoclonal antibody, TAB004, the authors injected a single dose of the engineered T cells to tumor-bearing mice, after the tumor had been established. They observed that, in comparison to the control group, the tumor growth was dramatically reduced and the reduction was maintained until the study endpoint at day 57. Further analysis showed that the modified CAR T cells that infiltrated the tumors expressed high levels of both CD25 and PD1, which, as noted by the authors, indicates further activation by in vivo tumor antigen stimulation from the glycosylated tumor form of MUC1 (tMUC1).
Then, to determine whether the effects of the modified CAR T cells could extend beyond 57 days, the authors conducted a similar experiment as noted above, but extended the study endpoint to 81 days. They observed that, in comparison to the control group, the therapy reduced tumor growth until the study endpoint. However, they also observed that the treated tumors started to increase their growth after approximately 60 days post-treatment. The authors note that this may be due to several possibilities including requiring more than a single treatment injection, the loss of tMUC1 in the remaining tumors that progressed, or the increased PD1 expression in the tumor infiltrating lymphocytes may block the anti-tumor response. They tested each possibility and found that the most likely solution to remain active would require additional injections of the therapy. In addition, the combination of CAR T cells and PD1 antibody enhanced the anti-tumor immune response.
Collectively, the data collected by the authors demonstrate the effectiveness of using a modified CAR T therapy to reduce TNBC tumor growth effectively, with minimal damage to normal cells. Moreover, they are exploring the use of this type of treatment against other tumor types as well as combining this therapy with others as potential treatments for solid tumors.
Rigorous scientific research is always pushing the boundaries of what science is capable of, as seen with the authors of this study. Not all research projects will end with FDA approval. However, it is a relentless research effort that gets us closer to a therapy or disease understanding. Utilizing solutions such as a comprehensive portfolio of mouse models, powerful services, and knowledgeable JAX scientists and study directors with experience testing the efficacy of CAR T cells and other therapies, can help execute your in vivo projects.
On-Demand Webinar: Caring for Immunodeficient Mice - from Nude to NSG™
On-Demand Webinar: Innovative Preclinical Research Using Humanized NSG ™ Mice
JAX Blog: CAR T Cell Therapy, are we there yet?
Allard, B. et al. (2018). Immunoncology-101: overview of major concepts and translational perspectives." Semin Cancer Biol. DOI: 10.1016/j.semcancer.2018.02.005 [PMID: 29428479].
Daniyan AF, Brentjens RJ., 2016. At the Bench: Chimeric antigen receptor (CAR) T cell therapy for the treatment of B cell malignancies. J Leukoc Biol. 100(6):1255-1264 [PMID: 27789538]
Day C-P, Merlino G., et al., 2015. Preclinical mouse cancer models: a maze of opportunities and challenges. Cell. 163(1):39-53. DOI: 10.1016/j.cell.2015.08.068
Park SH. et al., 2019 Differential Functions of Splicing Factors in Mammary Transformation and Breast Cancer Metastasis. Cell Rep.29(9):2672-2688.e7. doi: 10.1016/j.celrep.2019.10.110 [PMID: 31775037}
Posey AD Jr, Schwab RD, et al., 2016. Engineered CAR T Cells Targeting the Cancer-Associated Tn-Glycoform of the Membrane Mucin MUC1 Control Adenocarcinoma. Immunity. 44(6):1444-54. doi: 10.1016/j.immuni.2016.05.014 [PMID: 27332733]
Wang Y, Luo F, et al., 2017. New chimeric antigen receptor design for solid tumors. Front. Immunol. 8: 1934. doi: 10.3389/fimmu.2017.01934 [PMID: 29312360]
Zhou R, Yazdanifar M, Roy LD, Whilding LM, Gavrill A, Maher J, Mukherjee P. 2019. CAR T Cells Targeting the Tumor MUC1 Glycoprotein Reduce Triple-Negative Breast Cancer Growth. Front Immunol. 10:1149. doi: 10.3389/fimmu.2019.01149