In 1893, an intriguing medical breakthrough was made when patients with large, incurable cancers were injected with bacteria derived from skin infections. These patients showed significant improvement, marking the beginning of what we now know as cancer immunotherapy. Since then, this field has grown, focusing on how the immune system, which naturally fights infections and cancer, can be used to target cancer cells.
The Immune System's Role in Cancer
The body’s immune system is its most powerful defense against any kind of infection including cancer. For cancer cells to survive, multiply, and form tumors, they undergo a process of adapting. In doing so, cancer cells evade the immune system's detection and manipulate the body’s defenses to shield them rather than destroy them. Immunotherapy attempts to reverse this process, helping the immune system recognize and eliminate cancer cells.
A major advancement that has gained momentum over the past decade is known as immune checkpoint blockade. This technique focuses on the immune system’s natural "safety switches," which typically prevent excessive immune activity to protect healthy tissues. Cancer hijacks these checkpoints to protect itself, and immune checkpoint blockade works by blocking these safety switches with specially designed antibodies. This allows the immune system to restore its ability to target and destroy cancer cells.
Mutations and Immune Responses
Mutations in the genetic code often cause cancer. Cancers caused by exposure to harmful substances, such as melanoma (a type of skin cancer) and some colon cancers, tend to have a higher number of mutations. These types of cancers, known as "hot" cancers, are more easily identified by the immune system. As a result, immune checkpoint blockade therapy tends to be more effective in treating these high-mutation cancers, as the immune system can more readily detect and attack them.
However, immunotherapy is not universally effective. Cancers with fewer mutations, or "cold" cancers, are harder for the immune system to detect, and may not respond as well to immune checkpoint blockade.
Cell Therapy: Engineering Immune Cells
Another form of immunotherapy is cell therapy, which doesn’t depend on the natural activity of the immune system. Instead, it involves engineering immune cells in the lab to enhance the body's cancer-fighting abilities. Scientists take parts of the immune system and reassemble them in innovative ways to create new tools for battling cancer. One method involves modifying T-cells, a type of immune cell that typically combats viruses, to target cancer.
This technique, called CAR-T therapy, involves inserting a "chimeric antigen receptor" (CAR) into T-cells, turning them into specialized cancer fighters. One method involves modifying T-cells. The modified T-cells are programmed to target a specific marker on cancer cells, allowing them to seek out and destroy the cancer.
The Challenges of Immunotherapy
Despite its success, immunotherapy has faced significant obstacles. Both immune checkpoint blockade and CAR-T therapies have seen so much success that they have led to an over-reliance on these existing approaches, leaving less room for innovation. In the U.S., of the 11 approved immune checkpoint blockade treatments, nine target the same immune interaction. Similarly, all approved CAR-T therapies target only one of two markers found in blood cancers.
This narrow focus has limited the success of immunotherapy, particularly when it comes to solid tumors. Solid cancers, such as lung or breast cancer, create a hostile environment for immune cells. Their Darwinian adaptability allows them to suppress immune responses, making it difficult for CAR-T cells to penetrate and destroy the cancer effectively. As a result, reliance on a single technology, such as Car-T, has not delivered on its initial promise for treating solid cancers.
Additionally, CAR-T therapy is expensive, costing around £282,000 per patient in the UK. The time it takes to manufacture the engineered cells, often two to three weeks, creates a window where the patient’s disease can progress, diminishing the effectiveness of the treatment. These issues have led to declining confidence in the widespread applicability of CAR-T therapy.
Learning from the Past
This situation is not entirely new. In the 1950s, chemotherapy faced a similar lack of confidence due to single-drug treatments failing to produce lasting cures. However, by the 1960s, the introduction of combination chemotherapy, which uses multiple drugs simultaneously, began yielding better and more durable results. Today, multi-drug regimens are a fundamental component of cancer treatment.
Following a similar path, immunotherapy is now moving toward combination approaches. In a recent study at University College London, researchers showed that engineered immune cells, known as gamma-delta T-cells, could be used to deliver anti-cancer antibodies. These modified cells not only attacked cancer in mice but also activated other immune cells to join the fight. Importantly, gamma-delta T-cells can be safely extracted from healthy donors and used to treat multiple patients, paving the way for more accessible and quicker treatments.
The Road Ahead
There is renewed optimism as interest grows in developing cell therapies that can be prepared in advance and stored for future use. This advancement could eliminate the delays caused by manufacturing, allowing patients to receive immediate treatment, and reducing the chance of their disease worsening while they wait.
Moreover, moving away from single-axis immune interventions, such as relying solely on immune checkpoint blockade or Car-T in isolation could lead to more effective outcomes. The immune system is a highly intricate network, and treatments need to match this complexity in order to provide lasting benefits for patients.
In the past year, the number of clinical trials involving gamma-delta T-cells has doubled, making it one of the fastest-growing areas of immunotherapy research. These cells offer the potential to revolutionize treatment, providing quicker and more effective therapies that can tackle a broader spectrum of cancers, including those that have been resistant to existing treatments.
While immunotherapy has not yet fully delivered on its great promise, its evolution continues. The challenges faced by early treatments, such as immune checkpoint blockade and CAR-T therapy, have led to a broader understanding of the immune system’s complexities. By embracing combination approaches and developing more accessible cell therapies, the field is moving closer to its goal of defeating cancer. Just as chemotherapy transformed cancer treatment in the mid-20th century, immunotherapy has the potential to usher in a new era of durable, effective cancer care.
Though immunotherapy has yet to fully meet its great expectations, the field continues to evolve. The challenges faced by early treatments, such as immune checkpoint blockade and CAR-T therapy, have led to a broader understanding of the immune system complexities. Through the use of combination approaches and the creation of more readily available cell therapies, immunotherapy is making significant progress toward the goal of defeating cancer. Just as chemotherapy transformed cancer treatment in the mid-20th century, immunotherapy could usher in a new era of durable, effective cancer care.
