Immunotherapy Lessons Learned in Melanoma May Turn Tide in Other Tumors

Adil Daud, MD

The use of immunotherapy in cancer was solidified by the ample activity seen in patients with melanoma, said Adil Daud, MD. Nevertheless, a better understanding of the biology driving this benefit may help expand the reach of this therapy into those with less immunogenic tumors.

At Morristown Medical Center’s 7th Annual Joseph Calello Melanoma Scholar Presentation, Daud, a clinical professor in the Department of Medicine and director of Melanoma Clinical Research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center, highlighted the immunotherapeutic advances in melanoma and analyzed ways that researchers can turn cold tumors into hot ones.

In 2011, the FDA approved the use of ipilimumab (Yervoy) for patients with metastatic melanoma, thus launching an era of checkpoint inhibitors. However, ever since that approval researchers have struggled with understanding why melanoma triggers the immune system in ways that other cancers do not. Even before anti—CTLA-4 therapy came to the forefront of treatment, patients with melanoma experienced modest benefit from traditional immunotherapies, such as interleukin (IL)-2 and interferon (IFN), said Daud.

However, even after the use of single-agent ipilimumab was replaced by combination immunotherapy, there are patients with melanoma who still do not respond to this treatment. Moreover, responses to immunotherapy tend to be transient instead of durable. As such, ongoing research is being geared toward identifying biomarkers, additional immune checkpoints, and determining patient characteristics unrelated to the tumor that could be key to immune response, he added. Not only could this information bolster the role of immunotherapy in melanoma, but it could broaden its clinical applicability to other tumor types as well.

Resistance

As with every treatment approach, regardless of how effective it may be, the development of resistance is common. One theory for acquired and intrinsic resistance to immunotherapy lies in exhausted T cells. It is believed that as a tumor thrives in the body, the T cells eventually lose their memory-like state that allows for the body’s natural immune response.

“When you have a virus like measles or pneumonia, your T cells are activated,” explained Daud. “Then, when the virus goes away, those activated T cells remain in your body for life as memory T cells. If you develop a similar infection somewhere down the line, those T cells are there, and they proliferate. In cancer, the T cells don’t transition to that memory state.”

He added that while, for the most part, researchers cannot create tumor-active T cells, they can exploit exhausted tumor-active T cells.

In one study,¹ researchers indicated that low levels of partially exhausted cytotoxic T lymphocytes (peCTLs) in patients with melanoma were associated with higher overall response rate (ORR) to combination immunotherapy compared with anti—PD-1 monotherapy. In patients who were peCTL–high, there was no statistically significant difference observed in ORR between the 2 approaches. The study also suggested that peCTL was reduced in women and in those with liver metastasis.

It is widely understood that high PD-L1 expression corresponds with higher likelihood of benefit from anti—PD-1 therapy. A lesser known, but perhaps equally as effective biomarker in the melanoma space is IFNG, the gene encoding IFN-γ, according to recent studies. In one particular study,² which enrolled patients with melanoma and non—small cell lung cancer, 21 patients with melanoma received pembrolizumab (Keytruda). Median progression-free survival (PFS) with the PD-1 inhibitor was significantly longer in patients with high levels of IFNG compared with the low expressers (5.0 months vs 1.9 months; P = .0099). Furthermore, a significantly greater overall survival benefit was observed in those with higher levels of IFNG expression compared with those with lower levels (not reached vs 10.2 months; P = .0183).

“IFN-γ is a cytokine produced by the T cells when they are activated,” said Daud. “The more IFN-γ that is in your genes, the better your response will be. However, there is a lot of overlap for high expression of this in the nonresponders to immunotherapy.”

Liver Metastasis

Another area of research has been focused on liver metastasis. Studies have found that patients with melanoma who have these metastases may derive less benefit from anti—PD-1 therapy. For example, results from an analysis of patients with melanoma treated with pembrolizumab in the KEYNOTE-001, KEYNOTE-002, KEYNOTE-006 trials showed that liver metastasis was associated with reduced response and shortened PFS.³ Specifically, the ORR was 30.6% in patients with liver metastasis compared with 56.3% in patients without (P ≤.0001). Furthermore, the median PFS was significantly shorter in those with metastasis at 5.1 months compared with 20.1 months in those without metastasis. The presence of liver metastasis significantly increased the likelihood of disease progression (OR, 1.852; P <.0001).

“One theory here is that in adults, the function of the thymus is taken over by the liver, so that sets your level of tolerance,” explained Daud.

Turning Cold Tumors Hot

In terms of heating up cold tumors, preclinical work has suggested that successful anti—PD-1 therapy requires the presence of IL-12. In mouse models, researchers showed that in order to have effective antitumor responses, a subset of tumor-infiltrating dendritic cells that produced IL-12 was required.

These cells did not bind to PD-1, but produced IL-12 upon sensing IFN-γ that was released from neighboring T cells. Additionally, IL-12 appeared to stimulate antitumor T-cell immunity.⁴ As a result, several ongoing studies are taking patients who have failed multiple lines of therapy and treating them with anti¬—PD-1 therapy, while injecting their tumors with IL-12 via electric pulses. The hope is that this approach could increase the immunogenicity of the tumor, said Daud.

“IL-12 is a conduit between the innate immune system, the natural killer cells, and the adapted immune system, the T cells,” he added. “My theory, years ago, was that by driving more IL-12 into the tumor, we could make it hotter.”

In conclusion, Eric Whitman, MD, medical director of Atlantic Health System Cancer Care, said that there are many facets the oncology community does not yet understand in terms of why some patients respond to immunotherapy and others do not.

“The ongoing work that Dr Daud discussed could turn the tide in defeating not just melanoma, but other cancers as well,” he said.

References

1. Loo K, Tsai KK, Mahuron K, et al. Partially exhausted tumor-infiltrating lymphocytes predict response to combination immunotherapy. JCI Insight. 2017;2(14):93433. doi: 10.1172/jci.insight.93433.
2. Karachaliou N, Gonzalez-Cao M, Crespo G, et al. Interferon gamma, an important marker of response to immune checkpoint blockade in non-small cell lung cancer and melanoma patients. Ther Adv Med Oncol. 2018;10:1758834017749748. doi: 10.1177/1758834017749748.
3. Tumeh PC, Hellmann MD, Hamid O, et al. Liver metastasis and treatment outcome with anti-PD-1 monoclonal antibody in patients with melanoma and NSCLC. Cancer Immunol Res. 2017;5(5):417-424. doi: 10.1158/2326-6066.CIR-16-0325.
4. Garris CS, Arlauckas SP, Kohler RH, et al. Successful anti-PD-1 cancer immunotherapy requires T cell-dendritic cell crosstalk involving the cytokines IFN-γ and IL-12. Immunity. 2018;49(6):1148-1161.e7. doi: 10.1016/j.immuni.2018.09.024.