James P. Allison and the Discovery of CTLA-4: How Immune Checkpoint Blockade Revolutionized Oncology

Immuno-oncology has advanced significantly in recent decades, but when James P. Allison, PhD, first started attending American Association of Cancer Research (AACR) meetings in the 1970s, the field did not yet exist. It was Allison, Tasuku Honjo, MD, PhD, and their teams who unlocked the inhibition of negative immune regulation.¹

James P. Allison, PhD, is regental professor and chair of the Department of Immunology, the Olga Keith Wiess Distinguished University Chair for Cancer Research, director of the Parker Institute for Cancer Research, executive director of the Immunotherapy Platform, and director of the James P. Allison Institute at MD Anderson Cancer Center. Image Credit: MD Anderson Cancer Center

In Allison’s lab, his team uncovered the determination of the T cell receptor (TCR) structure and discovered that CD28 is a major costimulatory molecule that allows full activation of naïve T cells and prevents anergy in T-cell clones.² His lab was able to show that CTLA-4 inhibits T-cell activation by opposing CD28-mediated costimulation and that blockade of CTLA-4 could enhance T-cell responses, leading to tumor rejection in animal models.² This finding paved the way for the field of immune checkpoint blockade therapy for cancer.^1,2

In 1998, his lab developed ipilimumab (Yervoy; Bristol Myers Squibb), an antibody to human CTLA-4 that was the first immune checkpoint blockade therapy approved by the FDA in 2011. Following this, Honjo and his team discovered PD-1 as another target, which led to the development of PD-1 inhibitors. For their discovery of CTLA-4 and PD-1, Allison and Honjo received the Nobel Prize in Medicine in 2018.^1,2

Prior to the work of Allison and Honjo, scientists had been investigating mechanisms to engage the immune system in the fight against cancer for 100 years without success. After their discoveries, immune checkpoint therapy has revolutionized cancer treatment and fundamentally changed how cancer can be managed.³

However, Allison noted during his keynote presentation at the 2025 inaugural AACR Immunotherapy (IO) Conference that there is still much more work to be done in understanding how to treat the immune system to best fight cancer. According to Allison, immunotherapy does not have the goal of treating the tumor cell; instead, immunotherapy is treating the immune system.¹

“That made it very difficult to sell, actually. Nobody [sic] thought it could do that. But it also offered the positive side that it could be a universal cancer treatment,” Allison said during the AACR IO meeting in Los Angeles, California. “All [the tumor] has got to have is antigens. The [immune system] doesn't really care if it's a breast or prostate tumor or whatever, it just knows it shouldn't be there, and it's going to try and kill it.”¹

A depiction of immune checkpoint proteins expressed on T cells. Image Credit: © Corona Borealis - stock.adobe.com

After 10 years of data accumulated on the use of ipilimumab in patients with metastatic melanoma, Allison noted that 10-year survival outcomes were at approximately 20%.¹

“So, the question came up: Why aren’t 100% of patients alive at 10 years? Could be mechanistic, but of course the more interesting possibility is that there was another checkpoint,” Allison said. He explained that this led to the discovery of the PD-1 checkpoint by Honjo’s team, which allowed for the development of nivolumab (Opdivo; Bristol Myers Squibb), a PD-1 inhibitor.¹

In 2024, 10-year survival outcomes were assessed looking at ipilimumab monotherapy, nivolumab monotherapy, and combination ipilimumab and nivolumab in the treatment of patients with metastatic melanoma.¹ In this CheckMate 067 trial (NCT01844505), investigators observed a continued, ongoing survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy, in patients with advanced melanoma. Patients receiving the combination therapy had the longest median overall survival (71.9 months) compared to nivolumab alone (36.9 months) and ipilimumab alone (19.9 months). The hazard ratios for death favored nivolumab-based treatments over ipilimumab. Melanoma-specific survival exceeded 120 months for the combination therapy, with 37% of patients still alive at 10 years. Among those progression-free at 3 years, 10-year melanoma-specific survival was high across all groups (96% for combination therapy, 97% for nivolumab, and 88% for ipilimumab).^1,4

“We've gone from a disease which, when we started, the median survival was 7 months after diagnosis, and fewer than 3% of people were alive in 5 years, to where greater than 50% of people are alive at 10 years,” Allison said. “So that’s a great advancement.”¹

However, Allison noted that it’s important to realize that there are multiple different mechanisms of action present between CTLA-4 and PD-1 inhibitors.¹

“But since CTLA-4 is hardwired, it stops every T-cell response that you get. That’s it’s job—to stop the T cells from killing you,” Allison said.¹

For PD-1, Allison noted that it induces a resistance mechanism. Additional differences between CTLA-4 and PD-1 blockade are highlighted in Table 1.¹

“We showed in the 1990s doing a lot of in vitro work with peptides of different gradations that CTLA-4 lowers the threshold that's needed to get T-cells activated by peptides. So, you bring the lower-graded T cells into a response, predicting that that would expand the clonal diversity, and that's been shown both in animal models and in patients that you bring new T cells in [with CTLA-4], while PD-1 largely expands those cells that were already there that became exhausted as they responded,” Allison said.¹

CTLA-4 can also move T cells into cold tumors for prostate and kidney cancer, while PD-1 cannot do that. However, Allison noted that when CTLA-4 inhibitors and PD-1 inhibitors are given together, some of these challenges in variation of mechanism can be overcome.¹

“While CTLA-4 drives response, PD-1 takes the other brakes off,” Allison said. “But, of course, [together] they have more adverse events.”¹

According to Allison, although there remains more work to be done, it is important to acknowledge how far the field of immunotherapy has come since CTLA-4 was discovered 30 years ago in Allison’s lab.¹

“Before the advent of immuno-oncology, the way we did oncology was to take a whole lot of patients and look for P value. As you treat the patients, you see if you can move some subset of them over a significant amount and then declare victory—perhaps move them over from 7 months to 12 months,” Allison said. “With PD-1, there’s neoadjuvant trials now with response rates, both in lung cancer and in melanoma, at 70% for 3-year survival. So, we're getting there, but we know we can do better.”¹

REFERENCES

1. Allison JP. Celebrating 30 years of CTLA-4. Presented at: American Association of Cancer Research Immunotherapy; Los Angeles, California; February 22-26, 2025.

2. About Dr. Allison. MD Anderson Cancer Center. Accessed February 24, 2025. https://faculty.mdanderson.org/profiles/james_allison.html

3. The Nobel Prize in Medicine 2018 Awarded for Discovery of CTLA-4 and PD-1. ESMO. October 3, 2018. Accessed February 24, 2025. https://www.esmo.org/oncology-news/archive/the-nobel-prize-in-medicine-2018-awarded-for-discovery-of-ctla-4-and-pd-1

4. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med. 2025;392(1):11-22. doi:10.1056/NEJMoa2407417