Another Approach To Checkpoint Inhibitors: Targeting Receptors

In a previous story, I discussed a cancer advance called PD-1 checkpoint inhibitors which has proven effective yet imperfect against several tumors. The technology blocks a molecule widely found on white blood T cells. Yet, there is another way to achieve this effect. Normally, this structure interacts with a binding partner, just as a hand fits in a glove. Noting this, inhibitors can intercept the molecule (the hand) or its partner (the glove) to prevent the same interaction. This article will review inhibitors that target the partner receptor, known as PD-L1.

Checkpoint Proteins and Cancer 

Checkpoint inhibitors are antibody-based cancer therapies that unlock the immune system’s natural ability to fight cancer. These treatments work by blocking special proteins called immune checkpoints, found on the surface of white blood cells, especially T cells.

When checkpoint proteins bind to their partner receptors on cancer and other immune cells, they silence the T cells, stopping them from attacking threats. This mechanism plays an important role in maintaining immune balance. The proteins safeguard the body against overactive immune responses which could harm healthy tissues, as seen with several autoimmune diseases. However, cancer cells also co-opt this mechanism for their own purposes. Cancer cells bind to the checkpoints to quiet T cells that would otherwise retaliate, allowing the tumor to grow unrestrained.

A Second Approach: Targeting PD-L1

Checkpoint inhibitors free immune cells from these constraints. These drugs bind to checkpoint proteins before they can interact with their partner receptors. With the checkpoint blocked, the immune cell can rally against the tumor.

Early checkpoint inhibitors aimed at proteins found widely on T cells—specifically, CTLA-4 and PD-1. However, in 2016, a new type of inhibitor was introduced that targets PD-L1 (programmed death ligand 1), a protein overexpressed on cancer cells.

PD-L1 inhibitors disrupt the same immune mechanism as PD-1 inhibitors. They prevent PD-L1 proteins from binding to PD-1 on T cells. As illustrated in Figure 1, blocking either one of these checkpoints achieves the same goal. PD-1 can also bind to another receptor, PD-L2, but its therapeutic potential is still under investigation.

What Cancers Do They Treat?

Three anti-PD-L1 checkpoint inhibitors have been approved in the US: atezolizumab, by Genentech; durvalumab, by AstraZeneca; and avelumab, by EMD Serano. These inhibitors are effective in treating several types of cancers, especially those that express high levels of PD-L1 on the tumor surface. As Table 1 shows, each inhibitor treats different cancers, including bladder cancer, Merkel cell carcinoma, renal cell carcinoma and more.

Despite targeting the same immune axis, PD-1 and PD-L1 checkpoint inhibitors do not always benefit the same cancers. Some, such as a kind of soft tissue tumor called alveolar soft part sarcoma and small cell lung cancer, can only be treated with anti-PD-L1 inhibitors. Other cancers, including non-small cell lung cancer, hepatocellular carcinoma, and melanoma, could benefit from either type of inhibitor.

Combination Therapies

Anti-PD-L1 checkpoint inhibitors can be administered alone or synergized with other cancer treatments, including surgery, chemotherapy and targeted cancer drugs. They can even be administered alongside other checkpoint inhibitors. For example, patients with hepatocellular carcinoma or non-small cell lung cancer can take durvalumab alongside tremelimumab, a CTLA-targeting checkpoint inhibitor produced by the same company. This combination targets two distinct checkpoint interactions, enhancing the immune response against tumors.

Notably, the FDA has yet to approve any therapies that simultaneously target the PD-1 and PD-L1 axis. This is an active area of research for the field, although less popular than efforts to improve inhibitor synergy with other cancer treatments. A dual blockade could comprehensively address the PD-1/PD-L1 immune axis, enhance antitumor immunity and improve patient outcomes. However, patients could grow resistant to the treatment or experience stronger adverse effects by doubling down on the same immune interaction. Targeting distinct immune mechanisms appears more promising as a result.

Adverse Effects 

As a consequence of unleashing the immune system, checkpoint inhibitors characteristically stoke immune-related adverse effects. These autoimmune-like symptoms occur as the overactivated immune system harms health tissues and organs. The checkpoint mechanism can break self-tolerance and allow autoreactive T cells to attack healthy tissues expressing the same antigens as the tumor, as well as enhance T cell activation, proliferation, and cytokine production.

Commonly reported symptoms include fatigue, fever, chills, rash, skin itching, diarrhea, and hormone dysfunction such as hypothyroidism. In rare cases, inflammatory conditions can arise and impact the brain, liver, kidneys and heart. Other factors can also influence these adverse events, including risks of combination therapies or a patient’s pre-existing autoimmune condition.

While anti-PD-1 and anti-PD-L1 inhibitors spark similar adverse events, research on non-small cell lung cancer suggests that immune-related adverse events occur slightly less frequently with anti-PD-L1 inhibitors. Although lung inflammation is a relatively common adverse effect for both inhibitors, the incidence appears lower for PD-L1 inhibitors compared to anti-PD-1 inhibitors in non-small cell lung cancer.

Future Implications  

PD-L1 checkpoint inhibitors mark a significant milestone in the evolution of cancer treatment, offering new hope to patients battling various forms of cancer. By targeting the PD-L1 proteins on cancer cells, these innovative drugs effectively unleash the immune system’s innate ability to fight tumors. Their success in treating multiple cancer types, either alone or in combination with other therapies, underscores their transformative potential. While challenges remain, particularly with managing immune-related side effects, the future of PD-L1 inhibitors looks promising as research continues to refine and expand their applications.

Upcoming articles will discuss attractive routes of investigation: bispecific antibodies to improve PD-1 therapies, and experimental checkpoint inhibitors that target PD-L2, another binding partner to PD-1.


Read the original article on Forbes. 

© William A. Haseltine, PhD. All Rights Reserved.