Strengthen the Function and Infiltration of T Cells

T cells, especially tumor-infiltrating lymphocytes (TILs), play a determinant role in antitumor immune responses. As a potential strategy against resistance, strengthening function and infiltration of T cells is reported to result in durable tumor regression, including transfer of adoptive T cells, inhibition of negative molecules, and activation of stimulatory molecules. The specific and feasible means include chimeric antigen receptor T cells (CAR-T) therapy, costimulatory agonists, and inhibition of other immune checkpoints.

CAR-T Therapy

Chimeric antigen receptors (CARs, alias artificial T cell receptors, chimeric T cell receptors, or chimeric immunoreceptors) are receptor proteins individually designed to enable T cells to target a specific antigen, combining T cell activating functions and antigen-binding into a single receptor. CAR-T therapy generally includes 4 steps: 1) T cell collection, 2) T cell transfection, 3) T cell adoptive transfer, and 4) patient monitoring. Since CAR-T therapy promotes the function of effector T cells by strengthening the ability to detect and identify antigens expressed by tumor cells, it was considered as a strategy against resistance to immune checkpoint blockade caused by reduction of the function and infiltration of T cells.

It has been revealed by preclinical studies that the combination of ICBs and CAR-T synergistically leads to durable antitumor responses, improving survival possibilities in multiple cancers. For example, it was demonstrated that a combination of PD-1/PD-L1 axis blockade and CAR-T was more effective in inhibiting tumor development than monotherapy. Several clinical trials (NCT03182803, NCT03615313, and NCT02862028) on ICBs and CAR-T combinatory therapies are underway to be evaluated.

Fig.1 Schematic of the treatment of a patient with CAR T cells.¹

Costimulatory Agonists

In addition to co-inhibitory activities, costimulatory signals are essential for the maintenance of effector T cell function. Targeting immune-stimulatory receptors with antibodies has been proven to reverse immune resistance in many types of tumors, and a variety of drugs have been approved for the treatment of cancers.

For example, the synergistic reaction of 4-1BB agonist and PD-1 blockade was observed in a poorly immunogenic tumor model. However, another research reported that the presence of PD-1 blockade suppressed the anti-tumor activity of 4-1BB agonist in a model of spontaneous B-cell lymphoma, showing the complexity of the mechanisms and the need for further investigation. To date, several clinical trials have been ongoing to assess the safety and efficiency of Co-stimulatory agonist antibodies in combination with ICBs.

Inhibition of Other Immune Checkpoints

Inhibitory checkpoint molecules of different signaling pathways may interact and participate in the regulation of each other, thus affecting the activation and exhaustion of T cells and leading to the failure of ICBs. Previous evidence has shown that upregulation of other immunosuppressive molecules including LAG-3, TIM-3, TIGIT, BTLA, and VISTA are considered as the main cause of the resistance to PD-1/PDL1 and CTLA-4 blockades. Therefore, combination of these molecules with ICBs may be a prospective therapeutic strategy to deal with resistance. As mechanisms of various signaling pathways are being clarified, combination therapies of multiple immune checkpoint molecules have been studied in many preclinical models, resulting in tumor elimination through reversing the suppression of effector T cells. Additionally, the blockade of immune checkpoint using mAb may further reinforce the function of CAR-T cells via inhibition of immunosuppressive signaling pathways. Numerous clinical trials are currently ongoing to test the efficacy of antibodies against these inhibitory molecules alone or participate in combinatory therapy in cancer treatment.

Services at Creative Biolabs

Strengthening the function and infiltration of T cells is a promising strategy to deal with resistance to immune checkpoint therapy. Based on abundant experience and advanced technology platforms, Creative Biolabs provides professional services related to immune checkpoint to assist you in research, including but not limited to:

• Custom Immune Checkpoint Protein Development
• Antibody Development for Immune Checkpoints
• Immune Checkpoint Targeted Peptide Development
• Immune Checkpoint Targeted Small Molecule Drug Development
• Biomarker Development for Immune Checkpoint Inhibitor (ICI)
• Immune Checkpoint Assays
• Preclinical Research for Immune Checkpoint Targeting Drugs

If you are interested in any one of our services, please feel free to contact us for more details.

Reference

1. Jacobson, et al. "Time to put the CAR-T before the horse." Blood, The Journal of the American Society of Hematology 118.18 (2011): 4761-4762.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.