‘Goldilocks’ treatment window could lead to cancer therapy without harmful side effects

a) Rosetta fold, dock and design uses backbone fragments of natural MPs to construct symmetric, de novo architectures and an MP energy function (Weinstein et al., 2019) to optimize amino acid sequence. †b) Round 1 designs were biased toward the hydrophobic amino acid Leu relative to naturally occurring transmembrane domains (TMDs). In round 2, we included a sequence diversification step that reconciled the amino acid tendencies with those observed in natural TMDs. †c) The programmed membrane proteins (proMPs) strongly adhere to themselves in the E. coli inner membrane, as evidenced by high viability in the TOXCAT-β-lactamase (dsTβL) self-association assay with deep sequencing (Elazar et al., 2016a). The TMDs of human quiescine sulfhydryl oxidase 2 (QSOX2) and ErbB2 provide positive controls for TMD self-association, while the C-terminal portion of human L-selectin (CLS) provides a negative control. †d–f) Designed positions buried at the interface (orange) are more susceptible to mutation according to dsTβL analysis (Elazar et al., 2016a) (y– axis) then exposed positions (blue). Mutations are predicted as harmful or neutral/beneficial using computational mutation scanning of the model structures (materials and methods). Changes in self-association energies after mutation are calculated according to Equation 9. (g) proMPs produced as free peptides form SDS stable homo-oligomers. SDS-PAGE samples containing approximately 15, 45 and 135 g of peptide were heated to 95 for 1 minute and run under reducing conditions. * indicates the position of a minor contaminant of the fusion protein used to generate proMP peptides (Materials and Methods). The molecular weight under each gel is for a monomer of the corresponding peptide sequence with additional N-terminal EPE and C-terminal RRLC flanking sequences (Materials and Methods). †Hi) The 2.55 resolution structure (blue ribbon) determined from crystals grown in monoolein lipid cubic phase (LCP) shows that proMP 1.2, designed to form a dimer, associates to form a trimer in a lipid bilayer. surroundings. †i) Forward folding ab initio prediction of proMP 1.2 in trimeric (C3) symmetry results in a model structure (h, gray ribbon) which is very close to the experimental determined one. Credit: eLife (2022). DOI: 10.7554/eLife.75660″ width=”800″ height=”530″/>

Learning the rules for programming self-associating membrane proteins (MPs). †a) Rosetta fold, dock and design uses backbone fragments of natural MPs to construct symmetric, de novo architectures and an MP energy function (Weinstein et al., 2019) to optimize amino acid sequence. †b) Round 1 designs were biased toward the hydrophobic amino acid Leu relative to naturally occurring transmembrane domains (TMDs). In round 2, we included a sequence diversification step that reconciled the amino acid tendencies with those observed in natural TMDs. †c) The programmed membrane proteins (proMPs) are highly self-associating in the E coli inner membrane, as evidenced by high viability in the TOXCAT-β-lactamase (dsTβL) deep sequencing self-association assay (Elazar et al., 2016a). The TMDs of human quiescine sulfhydryl oxidase 2 (QSOX2) and ErbB2 provide positive controls for TMD self-association, while the C-terminal portion of human L-selectin (CLS) provides a negative control. †df) Designed positions buried at the interface (orange) are more susceptible to mutation according to dsTβL analysis (Elazar et al., 2016a) (Yes-axis) than exposed positions (blue). Mutations are predicted as harmful or neutral/beneficial using computational mutation scanning of the model structures (materials and methods). Changes in self-association energies upon mutation are calculated according to Equation 9. (g) proMPs produced as free peptides form SDS stable homo-oligomers. SDS-PAGE samples containing approximately 15, 45 and 135 g of peptide were heated to 95 for 1 minute and run under reducing conditions. * indicates the position of a minor contaminant of the fusion protein used to generate proMP peptides (Materials and Methods). The molecular weight under each gel is for a monomer of the corresponding peptide sequence with additional N-terminal EPE and C-terminal RRLC flanking sequences (Materials and Methods). †Hi) The 2.55 A resolution structure (blue ribbon) determined from crystals grown in monoolein lipid cubic phase (LCP) shows that proMP 1.2, designed to form a dimer, associates to form a trimer in a lipid bilayer. surroundings. †i) Forward-folding ab initio prediction of proMP 1.2 in trimeric (C3) symmetry results in a model structure (h, gray ribbon) which is very close to the experimentally determined. Credit: eLife (2022). DOI: 10.7554/eLife.75660

Researchers have developed a way to potentially reduce the toxic side effects of one type of immunotherapy, in findings that could overcome the breakthrough treatment’s biggest limitation.

CAR T-cell therapy is a new form of immunotherapy that amplifies a patient’s killer immune cells to attack and eliminate cancer.

It can be up to 90% effective in certain blood cancers and can even provide long-lasting remissions and cures in some patients. But a major limitation is the harmful side effects of the treatment, with about 50% of patients experiencing dangerous complications.

The new study, led by WEHI researchers in collaboration with Israel’s Weizmann Institute of Science, has designed a way to identify a “goldilocks” window that strikes a balance between safety and efficacy.

The team’s approach refines the cells used in the immunotherapy so that their activity is strong enough to eliminate the cancer, but not so strong as to cause toxic side effects.

The findings, led by WEHI’s associate professor Matthew Call and associate professor Melissa Call, are published in: eLife

Crucial Redesign

CAR T cell therapies involve collecting T cells from a cancer patient and charging the cells by individually redesigning them in the lab. These improved cells are then returned to patients.

The T cells are designed to produce proteins on their surfaces called chimeric antigen receptors (CARs), which act as artificial sensors that enable T cells to more efficiently recognize and bind to specific proteins on the surface of cancer cells.

Associate Professor Matthew Call said this synthetic sensor gives T cells the enhanced ability to attack and eliminate threats, such as cancer cells.

“While placing these supercharged T cells in a patient with a high tumor burden can be rapidly eradicated” cancer cellsit also creates the perfect storm for an ongoing toxic reaction that can be harmful,” said associate professor Call.

There is currently no way to reliably predict how strong CAR T cell therapy will be for a patient.

While previous studies have attempted to refine T cells by targeting the sensor’s end sections, which either bind to the cancer cell or direct the T cells to kill, the new research is the first to look at it from scratch. designing the center section.

Researchers took advantage of the computational expertise of the Weizmann Institute of Science to stitch together pieces of natural immune sensors with custom-designed synthetic elements, to generate new circuits that can be used to tune and assess variations of potency.

“By focusing on the connector fragment in the middle, we can generate different versions of CARs that we know are stronger or weaker, allowing us to tailor them to a patient’s potency requirements,” said associate professor Call.

“Being able to predictably tune this T-cell activity broadens our research considerably, unlike previous studies, as we focus on something that occurs in each immunotherapy scenario.

“For the first time, we can establish rules that apply to any cancer that uses CAR T-cell immunotherapy.”

'Goldilocks' treatment window could lead to cancer therapy without harmful side effects

A healthy human T cell. Redesigned T cells are returned to a patient during CAR T cell therapy. Credit: National Cancer Institute (NCI)

Improved treatment

Associate professor Melissa Call said the ability to refine T cells would dramatically reduce the number of patients with serious side effects of the treatment, including fever, high blood pressure and respiratory distress.

“CAR T-cell therapy has been shown to be effective in eradicating highly advanced leukemias and lymphomas, while also keeping the cancer at bay for many years, even after a patient has stopped taking cancer medications,” said associate professor Call.

“The therapy has incredible potential for cancer patients, but is currently being used as a last resort because of these potentially serious side effects.

“Our tools could fundamentally rethink how CAR T cell therapy is delivered by reducing a patient’s risk of exposure to harmful side effects. This could allow patients with a wide range of cancers to receive CAR T cell therapy much earlier in the treatment process.”

There are currently over 600 clinical trials of CAR T-cell immunotherapy, with the treatment already being used for several blood cancers

Researchers hope their new tool can be used to triage immunotherapy patients based on the level of potency they need in the early stages of their treatment and move the field closer to reaching that “goldilocks” treatment window for many different cancers. bring.

The next phase of research, supported by the NHMRC, the Leukemia Foundation, Cancer Australia and Hearts and Minds Investments Ltd and TDM Foundation, will focus on developing these findings into a clinical setting to see CAR T-cell therapy being used as a safer first-line treatment.


CAR T drives acute myeloid leukemia into submission in preclinical studies


More information:
Assaf Elazar et al, De novo-designed transmembrane domains tune engineered receptor functions, eLife (2022). DOI: 10.7554/eLife.75660

Journal information:
eLife


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