Combined Therapy of CTLA-4 and PD-1/PD-L1

Introduction to CTLA-4 and PD-1/PD-L1

CTLA-4 is crucial to the attenuation and early activation of naïve and memory T cells, priming cancer-specific T-cell immunity via interactions with ligands CD80 and CD84. In contrast, PD-1 plays a more prominent role in modulating T-cell activity in peripheral tissues via its interaction with PD-L1 and PD-L2. These two immune checkpoints are thought to be largely non-redundant, both spatiotemporally and in their immune effects. CTLA-4 can generally function as an early immune checkpoint, controlling T cell activation and induction of the consequently required metabolic switch, and PD-1 as a late immune checkpoint, which keeps previously activated antigen-specific T cells functionally and metabolically on hold.

Double Immune Checkpoint Blockade of CTLA-4 and PD-1/PD-L1

Despite the general success of checkpoint therapies, not all patients respond or achieve only partial tumor regression to anti-PD-1 or anti-CTLA-4 monotherapy. Preclinical models revealed that blocking CTLA-4 or PD-1 alone leads to upregulation of the unblocked pathway; hence, the efficacy of either monotherapy is limited by increased suppression of T cell responses through the other two pathways. Combination CTLA-4 and PD-1 blockade generally shows superior anti-tumor activity compared with each checkpoint blockade and has been a quite successful form of cancer immunotherapy.

Fig.1 Differences between CTLA-4 and PD-1 immune inhibitory pathways. (Zappasodi, 2018)

Combination of anti-CTLA-4 and anti-PD-1

A wide variety of treatment combinations are now under clinical development in diverse cancer types. An anti-CTLA-4 antibody is approved by FDA based on improvement in overall survival among patients with advanced melanoma, with objective responses in approximately 11% of the patients. In addition, an anti-PD-1 monoclonal antibody is approved by the FDA on the basis of an improvement in confirmed objective responses among patients with metastatic melanoma who have disease progression after treatment with an anti-CTLA-4 antibody or a BRAF inhibitor.

A recently reported phase I clinical trial with anti-CTLA-4 antibody in combination with anti-PD-1 antibody also demonstrated tumor regression in ~50% of treated patients with advanced melanoma, in most cases with tumor regression of 80% or higher. Phase II clinical trials involving combination treatment with anti-CTLA-4 antibody and anti-PD-1 antibody resulted in a higher response rate, more complete responses, and higher PFS in a phase III trial. Based on these promising results, the FDA approved the use of a combination of anti-CTLA-4 antibody and anti-PD-1 antibody in treatment for patients with unresectable or metastatic melanoma without a BRAF mutation in 2015. Still, optimization of this combination therapy is required to obtain clinical responses in a fraction of the patients above the current 60%. Overall, double immune-checkpoint blockade with anti-CTLA-4 anti-PD-1 is currently the most effective combination approach for treating solid cancers.

Fig.2 T-cell activation, inhibition and anti-CTLA-4/anti-PD-1 blockade mechanisms. (Marshall, 2018)

Services at Creative Biolabs

Combining state-of-the-art technology with personal service and attention, Creative Biolabs offers a series of custom services for immune checkpoint CTLA-4 and PD-1/PD-L1, including but not limited to:

Please do not hesitate to contact us for more detailed information.

References

Zappasodi, R.; et al. Emerging concepts for immune checkpoint blockade-based combination therapies. Cancer cell. 2018, 33(4), pp.581-598.
Marshall, H.T.; Djamgoz, M. Immuno-oncology: emerging targets and combination therapies. Frontiers in oncology. 2018, 8, p.315.

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