Overcoming Resistance to Checkpoint Inhibitor Cancer Therapy

(Posted on Friday, October 25, 2024)

Checkpoint inhibitors are a groundbreaking class of cancer treatment, but they come with two frustrating challenges. In some cases, tumors show no initial response, rendering the therapy ineffective from the outset. In others, tumors that respond early on can develop resistance, gradually undermining the treatment’s impact. Both scenarios leave doctors and researchers grappling with how to achieve durable control over cancer. This article explores the latest findings on what drives this resistance and how scientists are working to overcome it.

Checkpoint Inhibitors and Resistance

Checkpoint inhibitors are a novel breakthrough that unleash the immune system’s natural cancer-fighting abilities—mainly surveilling the body and eliminating any cancer cells it finds. This patrol could not be accomplished without checkpoints, proteins found on the surface of immune cells that signal when the cells should attack and when to stand down.

However, the immune system isn’t the only one with access to checkpoints. Cancer cells exploit these proteins for their own gain. When cancer cells bind to checkpoints, they force immune cells to shut down when they would otherwise attack, leaving cancer cells to grow without restraints.

For some patients, checkpoint inhibitors can help reverse cancer’s clever tactic. The antibodies in these inhibitors bind to checkpoint proteins before cancer cells can; this overrides the cancer’s “stop” signal and restores the immune system’s ability to identify and eliminate tumor cells.

But just as cancer cells mutate to grow and spread, they also evolve to resist these therapies.

Resistance can show up in different ways. Some patients do not respond to the therapy at all—this is called primary resistance. Others might initially respond, only for their cancer to stop responding after a few months, which is known as acquired resistance. In both cases, the outcome is the same: the immune system loses its ability to control the disease, and the cancer resumes its spread.

How Tumors Change & Grow Resistant 

Cancer’s shapeshifting qualities make it particularly difficult to target. Tumors can outsmart checkpoint inhibitors and the immune system in several ways.

1. Mutations in tumor cells: Some cancers develop mutations that change the very proteins targeted by the immune system, allowing the tumors to become invisible once again.
2. Loss of antigen presentation: Tumors rely on proteins called antigens to “flag” immune cells, marking them for destruction. But cancer cells can stop expressing these antigens, slipping past immune surveillance.
3. Creating a hostile environment: Tumors can also alter their surroundings to suppress the immune response. They might release chemicals that inhibit immune cells or recruit suppressive cells like regulatory T cells to shut down the attack.
4. Checkpoint redundancy: Blocking one checkpoint, like PD-1, may not be enough if the tumor starts exploiting other immune escape routes. The cancer can simply use a backup checkpoint, such as LAG-3 or TIM-3, to continue evading the immune system.

Exhaustion—How the Immune System Loses Steam 

Changes in cancer cells are only one part of the equation. Another contributing factor to treatment resistance stems from changes in the immune system.

Checkpoint inhibitors do not target cancer cells directly—they encourage immune cells to detect and remove cancer cells from the body. This means the treatment’s effect will weaken if the immune cells weaken.

This is why T cell exhaustion is a significant hurdle in overcoming resistance. Constant exposure to the unfriendly and immunosuppressive environment around the tumor impairs white blood T cells and forces them into an exhausted, dysfunctional state. When this happens, the T cells express additional immune checkpoints that slow their activity, and they become less efficient at recognizing and eliminating cancer cells. Patients with primary resistance may not respond to inhibitor therapy if their T cells are already forced into irreversible exhaustion.

Strategies to Counter Resistance

Cancers are constantly evolving and thwarting our best defenses. Despite the challenges, researchers are working to overcome resistance to checkpoint inhibitors.

One of the most effective approaches is targeting two distinct checkpoints at once. This shuts down multiple immune escape routes simultaneously. For example, it is possible to target PD-1 and CTLA-4 checkpoints using inhibitors such as nivolumab and ipilimumab. The combination therapy achieves higher response rates in patients with advanced melanoma, kidney cancer and certain lung cancers compared to treatment with a single inhibitor. This field of research could grow as scientists develop inhibitors that target other known immune checkpoints such as TIM-3 and TIGIT.

What if one treatment could do the work of two inhibitors? That’s the goal of bispecific antibodies, which target two immune checkpoints at once. One clinical trial reveals that their PD-1 and LAG-3-targeting antibodies can elicit a response in patients whose cancer has progressed after taking PD-1 targeting therapies. Still, heightened immune system activation from either therapy carries a trade-off: a higher risk of immune-related side effects.

Another promising avenue of research is combining checkpoint inhibitors with other cancer treatments such as chemotherapy, radiation, targeted therapies or immunotherapies like CAR T therapy. This multi-pronged approach weakens cancer’s defenses, leaving it more vulnerable to immune attack. For instance, administering chemotherapy with a PD-1 targeting inhibitor called pembrolizumab can achieve more durable responses than chemotherapy alone for patients with endometrial cancer and advanced lung cancer.

Personalized medicine may also offer potential solutions. The field aims to develop treatments that are tailored to the unique genetic makeup of a patient’s tumor. This involves using diagnostic tools to predict which patients might develop resistance or creating innovative methods to monitor tumor evolution in real time. Ideally, this information should allow doctors to modify treatment plans preemptively.

But sometimes, the problem isn’t that the cancer is invisible—it’s that the immune system becomes exhausted. In this case, rejuvenating exhausted immune cells could ensure the cells stay effective throughout treatment. This might involve giving patients immune-boosting drugs or using gene-editing technologies to enhance T cells’ ability to fight cancer. Therapeutics that influence the intestinal microbiome could also positively impact immune cell function, although this link is still being investigated.

Looking Ahead

Checkpoint inhibitors play a crucial role in treating advanced cancers, offering some patients years of control and transforming cancer into a manageable condition. However, these therapies are far from a cure-all. Resistance limits their effectiveness, requiring constant adjustments to treatment strategies. Fortunately, new therapies, combination approaches, and advances in personalized medicine are showing promise, equipping doctors with better tools to overcome resistant cancers.

Read the original article on Forbes