Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

CAR-T cells can detect antigens and activate cytotoxic activity to destroy tumor cells, and their efficiency is closely related to the differences in T cell function. Less differentiated T cells, such as naïve T cells (Tn), T memory stem cells (Tscm), and central memory T cells (Tcm), exhibit higher anti-tumor efficacy than CAR-T cells produced from T effector memory cells (Tem) and effector T cells (Teff).

Using a mixture of cytokines, researchers have shown that diverse phenotypes of T cells may be generated. As a result, choosing optimal cytokines or a combination of cytokines to cultivate T cells is a viable technique for increasing CAR-T cell effectiveness.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

Image Credit: ACROBiosystems

IL-15 can increase CD8+ T memory cell function and antitumor activity

When murine lymphocyte cells were cultivated and expanded in vitro in media containing IL-2 and IL-15, the findings revealed that T cells cultured with IL-2 primarily differentiated into T effector memory cells (Tem), whereas cells cultured with IL-15 primarily differentiated into central memory T cells (Tcm).

In terms of function, IL-15 encourages T cells to produce additional anti-tumor molecules, including IFN-γ, TNF-α, IL-10, IL-2, and so on.1

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

IL-15 prompts T cells to secrete more antitumor factors.
Proc Natl Acad Sci U S A. 2004 Feb 17; 101(7): 1969–1974. Image Credit: ACROBiosystems

IL-7+15 can increase T memory cell function and antitumor activity of CAR-T cells

IL-7+15 has a greater expansion impact on CD19-CAR-CD8+ T cells than IL-2 and aids in the retention of CD45RA and CCR7 expression. The effector function, as well as the anti-tumor activity of CAR-T cells, is also enhanced upon antigen-specific stimulation, which is accompanied by a considerable rise in IFN-γ secretion.2

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

CAR-T cells cultured with IL7+15 have stronger antitumor activity
Blood. 2014 Jun 12; 123(24): 3750–3759. Image Credit: ACROBiosystems

IL-7+15 expanded CAR-T cells have higher in vivo survival rate

Researchers consistently found that CAR-T cells exposed to IL-2 had a short half-life and vanished by day 3 post-infusion in NSG mice engrafted with a high tumor load of Raji cells and infused with CAR-T cells.

In contrast, however, IL-7 and IL-15 expanded CAR-T cells were detectable for more than 14 days after infusion and appeared to accumulate in the spinal cord, where tumor cells were primarily localized. Mice that were given IL-7 and IL-15 expanded CAR-T cells had substantial delays in disease/paralysis development.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

CAR-T cultured with IL-7+15 has long survival time and strong antitumor activity
Blood. 2014 Jun 12; 123(24): 3750–3759. Image Credit: ACROBiosystems

IL-15+21 can increase T memory cell function and antitumor activity of CAR-T cells

CAIX CARs were expanded using IL2, IL7 + 15, or IL15 + 21 in a study. The results showed that T cells multiplied best with IL-15+21, which promoted the higher expansion of CD8 + T cells and could thus generate activated CAR-T kill-activity.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

IL15+21 has the better effect of expansion T cells and enhance the ability of killing tumor
Hum Gene Ther Methods. 2014 Dec 1; 25(6): 345–357. Image Credit: ACROBiosystems

Finally, cytokines like IL-7, IL-15, IL-21, and IL-2 are critical in the development of cell therapy. These cytokines are critical raw materials in cell therapy and have a tight relationship to clinical therapeutic impact. The FDA and the Chinese Pharmacopoeia have relevant regulations for the usage of these critical materials.

The FDA CMC advises that materials be FDA-approved or clinical-grade. Priority must be given to the use of low-risk materials, including pharmaceutical grade and GMP grade materials, over non-GMP grade materials per Chinese Pharmacopoeia rules.

Since most raw materials are not accessible in the pharmaceutical stage, GMP grade is the first option for many pharmaceutical companies. However, it is important to consider how to confirm that the raw material is indeed GMP grade.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

Image Credit: ACROBiosystems

ACROBiosystems is dedicated to the creation of high-quality reagents for use in immune cell therapy clinical trials. Researchers have successfully created a range of high-quality GMP-grade cytokines such as IL-15, IL-7, and IL-21 to assist the cell therapy development process, based on the GMP-grade quality management system platform and cell therapy manufacturing criteria.

Product list

Source: ACROBiosystems

Molecule Cat.No. Product description Preorder/Order
IL-15 GMP-L15H13 GMP Human IL-15 Order
IL-7 GMP-L07H24 GMP Human IL-7 Order
IL-21 GMP-L21H25 GMP Human IL-21 Preorder

 

ACROBiosystems GMP quality management system

  • Secondary sterile filtration and aseptic method
  • Clean room of pharmaceutical class B+A and automated filling equipment
  • ISO 9001:2015 and ISO 13485:2016 compliance
  • The production plant is licensed to produce drugs

Animal-free materials

  • Raw and packaged materials are both recorded
  • Personnel who are qualified and well-trained
  • Quality assurance papers are evaluated and authorized by QA

Fully batch production and control records

  • Analytical method validation
  • Maintenance and calibration of equipment
  • Detailed regulatory support files

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

Automatic separation and purification system. Image Credit: ACROBiosystems

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

Automatic filling equipment. Image Credit: ACROBiosystems 

Partial quality release testing items

  • Host DNA residues
  • Sterility testing
  • Comprehensive stability data support
  • Purity
  • Cell activity
  • Endotoxin
  • In vivo safety verification
  • Host protein residue
  • Mycoplasma detection
  • In vitro virus assay
  • Lot-to-lot consistency testing

Verification data 

GMP IL-7/IL15 activity is calibrated against the WHO standard and can efficiently expand T cells.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

GMP Human IL-7 (Cat. No. GMP-L07H24) stimulates proliferation of PHA-P-activated human peripheral blood mononuclear cell (PBMC). The EC50 for this effect is 3.821 ng/mL, corresponding to a specific activity of > 1.0 × 10^8 IU/mg, which is calibrated against human IL-7 WHO International Standard (NIBSC code: 90/530) (QC tested). Image Credit: ACROBiosystems

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

GMP Human IL-15 (Cat. No. GMP-L15H13) stimulates proliferation of CTLL-2 cells. The EC50 for this effect is 1.004 ng/mL, corresponding to a specific activity of > 0.8 × 10^7 IU/mg, which is calibrated against human IL- 15 WHO International Standard (NIBSC code: 95/554) (QC tested). Image Credit: ACROBiosystems

GMP Human IL-15 (GMP-L15H13) has high batch-to-batch consistency.

Demonstrating how to enhance antitumor activity and overcome T cell exhaustion

Image Credit: ACROBiosystems

References

  1. Klebanoff CA, Finkelstein SE, Surman DR, et al. IL-15 enhances the in vivo antitumor activity of tumor-reactive CD8+ T cells. Proc Natl Acad Sci U S A. 2004;101(7):1969-1974. doi:10.1073/pnas.0307298101
  2. Xu Y, Zhang M, Ramos CA, et al. Closely related T-memory stem cells correlate with in vivo expansion of CAR.CD19-T cells and are preserved by IL-7 and IL-15. Blood. 2014;123(24):3750-3759. doi:10.1182/blood-2014-01-552174

About ACROBiosystems

ACROBiosystems is a leading manufacturer of recombinant proteins and other critical reagents to support the development of target therapeutics. The company employs an application-oriented development strategy, with a particular focus on product design, quality control, and solution-based support. Our products and services enable anyone in the field of drug development to have a more intuitive and streamlined process.

To respond to the coronavirus pandemic, ACROBiosystems has developed SARS-CoV-2 antigens specifically designed and optimized for serological test kits, including Spike-derived antigen S1, RBD, and Nucleocapsid protein. Proteins have been supplied to diagnostic companies in large quantities.


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Last updated: Aug 2, 2022 at 6:52 AM

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