Patient-derived micro-organospheres enable cutting-edge precision
oncology

Date:
May 5, 2022
Source:
Terasaki Institute for Biomedical Innovation
Summary:
Scientists develop micro-organospheric models to predict therapeutic
response accurately and rapidly, enabling cutting-edge precision
oncology.



FULL STORY ==========================================================================
A patient's tumor cell response to therapy is affected by many factors, including genetic alterations, tumor microenvironment, and intratumoral heterogeneity. This can make it extremely difficult to determine optimum treatment regimens, amidst the ever-increasing number of drug candidates
and cancer therapies that have recently been developed. Added to these challenges is the limited timeframe in which treatment decisions must
be made after diagnosis -- frequently on the order of two weeks or less.


========================================================================== Shortcomings of existing oncogenic models make them unsuitable for
clinical use. Patient-derived tumor cell lines change when sub-cultured, rendering them inaccurate as tumor models, and models made from
xenografts -- patient tumor cells injected into immuno-deficient mice
-- retain their characteristics but are time-consuming and costly to
produce. Patient-derived organoids, miniaturized 3D versions of tumor
tissues, lose the patient tumor microenvironment during sub-culturing,
and production of these organoids in a timely enough manner for clinical decision making remains unattainable.

These challenges have been addressed in a multi-organizational
collaborative effort, which included scientists from the Terasaki
Institute for Biomedical Innovation (TIBI) and Duke University, led by
TIBI's chief scientific officer and professor, Dr. Xiling Shen.

As outlined in their recent publication in Cell Stem Cell,the
team developed a droplet-based microfluidic technology to produce micro-organospheres (MOS) from cancer patient biopsies within an
hour. Patient tumor, immune, and connective tissue cells quickly form
miniature tumors that retain the original microenvironment within
thousands of these MOS, which can be used for testing many drug
conditions. Tests on MOS of various cancerous origins demonstrated
the retention of the cells' genetic profiles, as well as gene and immunosuppressive marker expression of the original tumor tissues.

Initial tests using MOS from a small cohort of metastatic colorectal
cancer patients were screened against a panel of therapeutic drug
candidates. When the drug sensitivity results were compared against actual clinical treatment outcomes, there was almost perfect correlation. What's
more, the MOS could be generated from small numbers of cells, as typically collected from biopsies, and the whole MOS generation and drug screening process took less than two weeks.

In a series of subsequent and elegant experiments, the researchers
developed assays to test the MOS response to immune therapies. They were successfully able to demonstrate that bispecific antibodies mobilize
resident immune cells in the original microenvironment to attack tumor
cells, an unprecedented achievement in immunotherapeutic screening. In
another series of experiments, the scientists tested their MOS against
the effects of combination immune therapies and were able to demonstrate
both predicted responses and optimization of multiple treatment regimens.

They were also able to observe effective penetration into the MOS
by activated T-cells and subsequent killing of the MOS tumor cells;
such T-cell infiltration was achievable due to the small size and large surface-to-volume ratio of the MOS droplets that mimic natural diffusion
limits within tissues, and could not be obtained using conventional
models.

The findings of the research team have tremendous implications for
the clinic.

With all the difficulties presented in developing cancer treatment models, their work fulfills many needs. Their methods to produce an accurate
tumor model from limited biopsy tissue in a timely and less costly manner
opens the door to a variety of testing avenues for drug and immune
therapies. The automation of MOS production ensures reproducibility,
which is a requirement by the FDA.

"The technology developed here is a groundbreaking advancement
in physiological modeling for solid tumor diseases and personalized
medicine," said Ali Khademhosseini, Ph.D., TIBI's Director and CEO. "It is
sure to have a highly significant impact in the clinic." Authors are:
Shengli Ding, Carolyn Hsu, Zhaohui Wang, Naveen R. Natesh, Rosemary
Millen, Marcos Negrete, Nicholas Giroux, Grecia O. Rivera, Anders Dohlman, Shree Bose, Tomer Rotstein, Kassandra Spiller, Athena Yeung, Zhiguo Sun, Chongming Jiang, Rui Xi, Benjamin Wilkin, Peggy M. Randon, Ian Williamson, Daniel A. Nelson, Daniel Delubac, Sehwa Oh, Gabrielle Rupprecht, James
Isaacs, Jingquan Jia, Chao Chen, John Paul Shen, Scott Kopetz, Shannon
McCall, Amber Smith, Nikolche Gjorevski, Antje-Christine Walz, Scott
Antonia, Estelle Marrer- Berger, Hans Clevers, David Hsu, Xiling Shen.

This work was supported by funding from the National Institutes of Health
(U01 CA217514, U01 CA214300) and the Duke Woo Center for Big Data and
Precision Health.


========================================================================== Story Source: Materials provided by Terasaki_Institute_for_Biomedical_Innovation. Note: Content may be edited
for style and length.


========================================================================== Journal Reference:
1. Shengli Ding, Carolyn Hsu, Zhaohui Wang, Naveen R. Natesh, Rosemary
Millen, Marcos Negrete, Nicholas Giroux, Grecia O. Rivera,
Anders Dohlman, Shree Bose, Tomer Rotstein, Kassandra Spiller,
Athena Yeung, Zhiguo Sun, Chongming Jiang, Rui Xi, Benjamin Wilkin,
Peggy M. Randon, Ian Williamson, Daniel A. Nelson, Daniel Delubac,
Sehwa Oh, Gabrielle Rupprecht, James Isaacs, Jingquan Jia, Chao
Chen, John Paul Shen, Scott Kopetz, Shannon McCall, Amber Smith,
Nikolche Gjorevski, Antje-Christine Walz, Scott Antonia, Estelle
Marrer-Berger, Hans Clevers, David Hsu, Xiling Shen. Patient-derived
micro-organospheres enable clinical precision oncology. Cell Stem
Cell, 2022; DOI: 10.1016/j.stem.2022.04.006 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/05/220505154455.htm

--- up 9 weeks, 3 days, 10 hours, 50 minutes
* Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3)