It’s been 15 years since we first saw clear evidence that an immune checkpoint inhibitor, specifically anti-CTLA-4, could increase survival rates for patients with advanced melanoma. This was a significant moment, leading to its FDA approval and marking cancer immunotherapy as Science Magazine’s 2013 Breakthrough of the Year. This breakthrough unleashed T cells in a way that offered improved outcomes for many patients facing hard-to-treat cancers. That year, we also saw promising results from another checkpoint inhibitor, anti-PD-1, and advancements in CAR therapy, which uses engineered T cells.
Now, however, we are witnessing an explosion of new research, clinical trials, and a wealth of potential treatments in the realm of immunotherapy—though it comes with an array of complex acronyms like ADCs, CAR-T, and others that can be daunting. The aim of this discussion is to take stock of where we are today and how far we’ve come. In a nutshell, we’ve made significant strides.
The key takeaway is that we can never have too many options for enhancing the immune response against cancer. For long-lasting success and potential cures, it seems that combinations of different immunotherapy classes will often be necessary. The hopes for harnessing the immune system to prevent cancer in high-risk individuals is particularly exciting.
In this overview, I won’t delve into nuances of each immunotherapy type, particularly the serious side effects that can arise, like cytokine release syndrome. Instead, I’ll focus on the general progress being made and the direction we’re heading in.
Currently, there are over 2,500 drugs and programs aimed at cancer immunotherapy available. Survival extensions from these treatments vary widely—from a few months to about a year and a half—depending on the type of cancer, prior treatments, and individual biology. Among these, Keytruda (pembrolizumab), a PD-1 inhibitor, stands out with over 40 FDA-approved uses, making it the top oncology drug globally. Unfortunately, many patients still experience only short-term improvements, signaling a need for more effective strategies.
Recent studies have suggested that short-term fasting might enhance the effects of immune checkpoint inhibitors, yet this doesn’t resolve the overall issue of limited benefits for most patients. This is why new checkpoint inhibitors are in clinical trials, aiming to help delay or prevent resistance. A recent approval involved a drug targeting LAG-3 in combination with a PD-1 inhibitor for advanced melanoma.
Oncolytic virus therapies are another promising avenue. These treatments aim to stimulate the immune system to target cancer cells, with the first FDA approval (T-VEC) granted in 2015 for use in unresectable melanoma. A number of viral agents are currently in development.
The current landscape includes over 15 approved antibody-drug conjugates (ADCs) and more than 300 in development. These ADCs are now being tested in combination with immune checkpoint inhibitors, as their different mechanisms may complement each other. BiTEs function by linking tumor cell antigens with T cells to prompt rapid cancer cell destruction, with 9 approved for various blood cancers and many more on the horizon.
Moving to T cell therapies, the process of engineering T cells has evolved significantly. The first approval was in 2017, focusing on blood cancers, but solid tumors have been challenging. Recently, tumor infiltrating lymphocytes (TILs) were approved for melanoma, with ongoing exploration into using natural killer (NK) cells and CAR-macrophages, among other strategies.
Cancer vaccines fall into two categories: treatment and prevention. There’s growing evidence for their effectiveness against difficult cancers like pancreatic and glioblastoma. Personalized mRNA vaccines are showing promise in inducing strong T cell responses, especially for triple-negative breast cancer. Efforts are also underway to simplify the vaccine process, exploring non-personalized options.
An intriguing area is “interception vaccines,” which target individuals with hereditary risks. The recent success of an off-the-shelf neoantigen vaccine for Lynch syndrome illustrates this.
How do we choose the most effective therapy among the numerous options available? Questions arise about the timing of immunotherapy, the reliability of biomarkers, and whether traditional treatments are necessary to prepare the ground for immunotherapy to be effective.
We also lack a comprehensive way to assess individual immune functionality in clinical settings. Recent advancements indicate that insights from the thymus can significantly improve predictions on responses to immune checkpoint inhibitors—a concept that had been overlooked for years. Additionally, there’s a growing need to evaluate the tumor microenvironment—understanding the cellular dynamics around tumors could provide crucial insights for therapy.
An exciting breakthrough allows for non-invasive assessments of the tumor environment through blood samples, offering valuable predictions for immunotherapy responses. The importance of this cannot be overstated, especially as we explore the complex landscape of pancreatic pre-cancerous lesions.
Looking ahead, the potential for preventive or interceptive vaccines is expanding, particularly for those with high genetic risk. The concept of “promolytics,” which addresses specific tumor-promoting clones, could redefine how we approach cancer prevention.
In summary, the field of cancer immunotherapy is flourishing, and we’re starting to appreciate the central role of the immune system in combating this disease, with ways to assess individual immune health growing ever more sophisticated. The future of immunotherapy holds great promise, and as we continue to develop strategies, there is hope for more effective and accessible cancer treatments.
