Anti-WT1 CAR-T Preclinical In Vivo Assay

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Target Background

Wilms'tumor 1 (WT1) encodes a transcription factor consisted with four zinc-finger motifs at the C-terminus and a proline/glutamine-rich DNA-binding domain at the N-terminus, which physiologically plays an essential role in the cell growth and differentiation, especially in the normal development of the urogenital system. In the matter of biological distribution and related pathology, WT1 is expressed in the normal mammary duct and lobule and mutated in a subset of patients with Wilms'tumor for the namesake and causes an embryonic malignancy of the kidney with the incidence of 1 in 10,000 infants. Although the WT1 was originally identified as a tumor suppressor, the subsequent reports demonstrated the significant high expression of WT1 in various hematological malignancies such as acute myelocytic and lymphocytic leukemia, chronic myelocytic leukemia and solid tumors including the gastrointestinal and pancreaticobiliary system, urinary tract, male and female genital organs, breast, lung, brain, skin, soft tissues and bone. Furthermore, the WT1 has been demonstrated not only as a diagnostic but also a robust prognostic marker in acute myeloid leukemia, colorectal cancer, breast cancer and high-grade serous ovarian carcinoma. In addition, the WT1 is ranked by the National Cancer Institute (NCI) as the No. 1 target for cancer immunotherapy. Therefore, the WT1 manifests great potentials as a target for CAR-T cell therapy.

Physiological function of WT1 for maintaining adult tissue homeostasis

Physiological function of WT1 for maintaining adult tissue homeostasis
Trends in Genetics 28.10 (2012): 515-524

Anti-WT1 CAR-T Cell Therapy

As for WT1 immunotherapy, multiple phase1/2 clinical trials have been completed for determining the safety, effectiveness and side effects of WT1 vaccine (NCT00923910), the WT1 antigen-specific cancer immunotherapeutic (WT1 ASCI) as post-induction therapy (NCT01051063) or post-consolidation (NCT00725283) therapy in multiple WT1-positive hematological malignancies, including AML, ALL, CML, etc. However, there is still no effort made for anti-WT1 CAR-T cell therapy via WT1 target currently. Creative Biolabs helps acute researchers break all the obstacles of pre-clinical study, and occupy the virgin land of anti-WT1 CAR-T cell therapy.

Animal Models for in vivo Study of anti-WT1 CAR-T Cell Therapy

Creative Biolabs offers almost all animal models for the preclinical in vivo studies for all kinds of hematological malignancies such as acute myelocytic and lymphocytic leukemia and chronic myelocytic leukemia, and solid tumors including the gastrointestinal and pancreaticobiliary system, urinary tract, male and female genital organs, breast, lung, brain, skin, soft tissues and bone. Take leukemia model as an example:

Carcinogen-Induced Models: animals from susceptible strains are exposed to carcinogenic chemicals or ionizing radiation following the development of leukemia;
Mosaic, Transposon, and Viral Induced Models: mosaic models are generated via virus infection or transposon, which integrates an oncogene of interest into the host genome resulting in expression of oncogene, aberrant expression of proto-oncogenes or disrupting of a cellular tumor suppressor;
Transgenic Models: inject or electroporate engineered targeting vector expressing the transgene of interest into murine ES cells, which subsequently are injected into tetraploid blastocysts and then transplant them into pseudopregnant surrogate mothers;
Xenograft Models: directly inject primary patient samples or human cell lines into immunocompromised host animals, which have been frequently exposed to ionizing radiation prior to sample injection to suppress any residual immune function.

The major techniques for generating animal models of leukemia

The major techniques for generating animal models of leukemia
Cancer and Metastasis Reviews 32.1-2 (2013): 63-76

Furthermore, Creative Biolabs provides assistance in creating clinically relevant animal models with customized requirements.

In vivo Assay Parameters and Techniques

At Creative Biolabs, we offer the most exquisite and comprehensive service platform for preclinical WT1 CAT-T cell therapy research.
Efficacy Test
Tumor remission monitored by tumor volume recording or bioluminescence imaging and survival curve tracking
Viability and Bio-distribution Studies
Durability, GLP-compliant bio-distribution studies
Toxicity Evaluation
Pilot tolerability (MTD, The route of administration, Dose regimen/response/onset)
Clinical observation (body weight, feed consumption, ophthalmologic and clinical pathology)
Cytokine storm surveillance (fever, hypertension, prolonged cytopenia)
Complete necropsy, organ weight
Histopathology
Tumorigenicity study

To unceasingly offer researchers convenience and assistance with the rapid scientific and technological progress, Creative Biolabs is dedicated to establishing the most reliable and relevant animal models in order to meet the rigorous requirements of preclinical studies for IND application. Beyond that, we are pleased to design studies together with our customers and provide customized service. Creative Biolabs fuels your research voyage with next century's pace. Please feel free to contact our customer service for more information.

References

Taube, Eliane Tabea, et al. "Wilms tumor protein 1 (WT1)—Not only a diagnostic but also a prognostic marker in high-grade serous ovarian carcinoma." Gynecologic oncology 140.3 (2016): 494-502.
Niavarani, Ahmadreza, et al. "A 4-gene expression score associated with high levels of Wilms Tumor-1 (WT1) expression is an adverse prognostic factor in acute myeloid leukaemia." British journal of haematology 172.3 (2016): 401-411.
Chau, You-Ying, and Nicholas D. Hastie. "The role of Wt1 in regulating mesenchyme in cancer, development, and tissue homeostasis." Trends in Genetics 28.10 (2012): 515-524.
Cook, Guerry J., and Timothy S. Pardee. "Animal models of leukemia: any closer to the real thing?" Cancer and Metastasis Reviews 32.1-2 (2013): 63-76.