Combination of Immune Checkpoint Therapy with Other Immunotherapy

Immune checkpoint molecule has been recognized as a promising anti-cancer target, and its incorporation with other therapeutic regimens has attracted considerable interest in the biological and preclinical study. Besides, immune checkpoint blockade (ICB) will increase the amplitude of therapeutic cancer vaccine-mediated activated T cell responses in the tumor microenvironment (TME). Cell-based immunotherapy, such as chimeric antigen receptor T (CAR-T) cell therapy, has attracted attention due to its ability to use specially altered T-cells to target cancer cells directly and precisely.

Combination of Immune Checkpoint Therapy with Cellular Immunotherapy

Immune checkpoint inhibitors are the most promising therapeutic approaches to activating antitumor immunity. However, single-agent immunotherapy is limitedly effective, so researchers are developing synergistic combinations of immunotherapies to stimulate immune responses adequately and specifically. Cell-mediated immune response against tumor cells can be enhanced by ICB, leading to the generation of a long-term memory lymphocyte population to patrol the body to attack the growth of any new tumor cells, thereby sustaining the therapeutic effects.

Fig.1 Mechanism of action of CAR-T with PD-1/PD-L1 blockade. (Xu, 2018)

Investigations have demonstrated that blocking immune checkpoints for reversing immunosuppressive TME is a promising approach to increase the beneficial effect of CAR-T treatment in solid tumors. Chen et al. demonstrated that PD-1 blockade by both anti-PD-1 antibody and PD-1 dominant negative receptor (PD-1 DNR) augmented CAR T-cell efficacy. Besides, multiple co-inhibitory receptors (e.g., TIM-3, LAG3, and TIGIT) can simultaneously target multiple inhibitory pathways and further enhance CAR T-cell potency.

Combination of Immune Checkpoint Therapy with Cancer Vaccine

Therapeutic cancer vaccines are being studied in combination with additional treatment modalities, such as immune checkpoint therapy, to compensate for the induced weak immune response when used alone. Growing preclinical data has revealed that combining cancer vaccines and immune checkpoint inhibitors can prime intensified immunogenicity and modulate immunosuppressive TME to improve clinical outcomes.

Fig.2 Cancer vaccines can be put to application in combination with immune checkpoint inhibitors. (Ye, 2018)

Karyampudi et al. used anti-PD-1 antibody and a multi-peptide vaccine (consisting of immunogenic peptides derived from breast cancer antigens, neu, legumain, and β-catenin) as a combination therapy regimen for the treatment of breast cancer-bearing mice. They observed enhanced antigen responses and a prolonged survival period. They suggested that PD-1 blockade can enhance breast cancer vaccine efficacy by altering both CD8 T cell and DC components of the TME.

Combination of Immune Checkpoint Therapy with Immune Stimulating Agents

To enhance the effectiveness of immune checkpoint therapy and overcome the resistance mechanisms in clinical, researchers are exploring the use of immune stimulating agents in combination with ICIs. Because the immune stimulating agents work by activating the immune system to improve the recognition and killing of cancer cells when introduced into the tumor microenvironment. The combination of immune checkpoint therapy with immune stimulating agents will be a promising approach in cancer treatment.

Combination of Immune Checkpoint Therapy with Anti-Angiogenic Agents

Recent research suggests that combining immune checkpoint inhibiters with anti-angiogenic drugs could be a promising therapeutic method for improving the efficacy of ICIs. Combination therapy also helps to remodel the immunosuppressive environment, which improves the anti-tumor effects of both drugs.

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References

1. Xu, J.; et al. Combination therapy: A feasibility strategy for CAR‑T cell therapy in the treatment of solid tumors. Oncology letters. 2018, 16(2): 2063-2070.
2. Chen, N.; et al. CAR T-cell intrinsic PD-1 checkpoint blockade: A two-in-one approach for solid tumor immunotherapy. Oncoimmunology. 2017, 6(2): e1273302.
3. Ye, Z. L.; et al. Cancer vaccine: learning lessons from immune checkpoint inhibitors. Journal of Cancer. 2018, 9(2): 263.
4. Karyampudi, L.; et al. Accumulation of memory precursor CD8 T cells in regressing tumors following combination therapy with vaccine and anti-PD-1 antibody. Cancer research. 2014, 74(11): 2974-2985.

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