Cancer immunotherapy has provided hope and life to many patients who have run out of options. While breakthroughs in treatment are hailed for their contribution to the largest single-year drop in cancer mortality in metastatic melanoma (from 2016-2017),1 immunotherapy still fails more often than it succeeds.

Now, researchers at the University of California, Los Angeles (UCLA) Jonsson Comprehensive Cancer Center have found that inhibiting the kinase PAK4 improves the effectiveness of PD-1 blockade immunotherapy in melanoma cells. The work was published in thejournal Nature Cancer.2

“We wanted to understand why some patients did not respond,” said Gabriel Abril-Rodriguez, PhD, the paper’s first author. First, he sequenced RNA from biopsies of patients with melanoma, looking for differences between responders and nonresponders. But when no distinct features emerged between the 2 groups, Dr Abril-Rodriguez tried a different approach. He compared the gene expression of melanoma tumors that were well infiltrated by immune cells with those that kept immune cells out.

Tumors characterized as “hot” or “cold” refers to the inflammation that occurs when T cells successfully penetrate the tumor. Only hot tumors are susceptible to PD-1 blockade immunotherapy, which works by removing the molecular shackles placed on T cells by the PD-1 protein. Blocking PD-1 frees the T cells to kill cancer cells. But if no T cells are getting into the tumor, then blocking PD-1 has no effect.

“Knowing that, we decided to focus on this variable, ‘infiltration: yes or no,’ which might be more clear and more simple,” said Dr Abril-Rodriguez. Sequencing revealed a list of genes whose expression differed between the infiltrated and noninfiltrated tumors.

The kinase PAK4 stood out as a good candidate for inhibition in the future, Dr Abril-Rodriguez said. It’s known to participate in the WNT signaling pathway, which plays a role in immune suppression. “The fact that PAK4 played a role in this pathway that has already been associated with immune-cell exclusion made it really appealing for us,” Dr Abril-Rodriguez said. And from a practical standpoint, an inhibitor targeting PAK4 is already available and in phase 1 clinical trials (ClinicalTrials.gov Identifier NCT02702492).

To test whether immunotherapy would work better with PAK4 out of the way, the researchers first disabled PAK4, using CRISPR-Cas9, in a PD-1–resistant melanoma cell line. Then they injected the melanoma cells into mice. Without PAK4, the melanomas responded to anti–PD-1 immunotherapy, the team reported.

Next, they obtained the PAK4 inhibitor, KPT-9274, from Karyopharm Therapeutics. Inhibiting PAK4 with the drug overcame the diseases’ resistance to anti–PD-1 immunotherapy, just as deleting the relevant gene had.

Giving the PAK4 inhibitor to mice in combination with anti–PD-1 immunotherapy slowed the growth of the melanomas more than either drug alone.

“If this holds true in the clinic, it would be a significant step forward for a proportion of patients who have traditionally been excluded from this benefit,” said Roxana Dronca, MD, of Mayo Clinic, Jacksonville, Florida, who was not involved in the work. Although the results still need to be replicated in human tumors, she said, “this is a great start.”

“Another interesting finding was the fact that this was found to be relevant across a few tumor types, not only melanoma, which is extremely important,” Dr Dronca said. She pointed out that in melanoma, around 50% of patients respond to immunotherapy, while in other tumor types, such as prostate cancer or glioblastoma, the response rate is only around 5%. “Clearly, in a lot of the tumor types there is a long way to go to make immunotherapy effective in a greater proportion of patients,” Dr Dronca said.

In addition to melanoma, the researchers tested a colon adenocarcinoma cell line that partially responds to immunotherapy. Combining anti–PD-1 with anti-PAK4 therapy, they found, slowed tumor growth even more than anti–PD-1 alone.

If the findings hold up, Dr Dronca said, “this will provide significant opportunity for us to increase responsiveness in cancers that have traditionally been resistant to anti–PD-1 treatment.”

Clinical trials will determine whether inhibiting PAK4 could have negative side effects, but theoretically, there’s no obvious reason it would. “PAK4 does a lot of things to drive cell proliferation and survival,” said Jonathan Chernoff, MD, PhD, chief scientific officer of the Fox Chase Cancer Center, in Philadelphia, Pennsylvania. “Generally, you don’t want a lot of it around.”

In the cell, PAK4 stabilizes another protein called beta-catenin, which is associated with T-cell exclusion. “There’s evidence that catenin is related to immune responses,” Dr Chernoff said. “It’s good to see their results were in line with the previous model.”

But the possibility remains that the PAK4 inhibitor used in the study may be acting via some other mechanism, Dr Chernoff cautioned. The drug also inhibits another enzyme, called NAMPT. “It could have all kinds of effects that we don’t know about,” Dr Chernoff said, “but at least in clinical trials, so far, they haven’t reported undue toxicities.”

Despite the issues with the particular compound tested in the paper, Dr Chernoff said, the work is valuable because it describes a potential mechanism by which PAK4 inhibits immune infiltration and influences outcomes. It “establishes a rationale for targeting this kinase with inhibitors in combination with immune checkpoint inhibitors,” he wrote, in a recommendation for F1000Prime.3

Though PAK4 inhibitors won’t likely make every tumor vulnerable to immunotherapy, they may provide an additional tool in the toolbox for clinicians to try. “We know other mechanisms have already been published, and I think they apply to a proportion of patients,” said Dr Dronca. “Let’s say we identify 8 to 9 different mechanisms, and we have a panel of markers to test for them, and from that we identify the combination that is relevant for the patient in front of us,” she said. “I believe this will be the true meaning of personalized therapy.”

Disclosure: Some of the authors of the original study disclosed financial relationships with pharmaceutical and medical device companies, and some are inventors in a patent application covering the use of PAK4 inhibitors for cancer immunotherapy. For a full list of disclosures, please refer to the original study.

References

  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7-30.
  2. Abril-Rodriguez G, Torrejon DY, Liu W, et al. PAK4 inhibition improves PD-1 blockade immunotherapy. Nat Cancer. 2020;1:46-58.
  3. Chernoff J. F1000Prime recommendation of [Abril-Rodriguez G et al., Nat Cancer 2019 1:46–58]. In F1000Prime, 09 Jan 2020. doi: 10.3410/f.737052640.793569227. Accessed January 24, 2020.