Combinations, Ex Vivo Manipulation May Be Key to Enhancing T-Cell Activity in Lung Cancer

Roy S. Herbst, MD, PhD

Investigational approaches aimed at transforming the tumor microenvironment for patients with lung cancer are going to be especially important as immunotherapy moves into the curative setting, explained Roy S. Herbst, MD, PhD. These include, for example, in vivo approaches with combinations that can generate an immune response such as ramucirumab (Cyramza) plus pembrolizumab (Keytruda) and ex vivo approaches that allow for external manipulation of T cells including cellular therapy could be potential ways of overcoming a cold tumor microenvironment.

“Over my 25 years [of being a thoracic oncologist], we’ve seen great activity and improvement in the treatment of patients with metastatic lung cancer. Immunotherapy is phenomenal, but even in the best case, [only] 10% to 15% of patients have amazing immune responses,” said Herbst, ensign professor of medicine (medical oncology) and professor of pharmacology at the Yale School of Medicine, in an interview with OncLive^® during the 23rd Annual International Lung Cancer Congress^®.

“We know that [immunotherapy] works, but we [also] know that it doesn’t work in some patients. There are mechanisms of resistance. The lack of [a] target can be one, but also the immune microenvironment is probably the major one. We have to find ways to get T cells more integrated and active in the tumor microenvironment.”

In the interview, Herbst, who is also director of the Center for Thoracic Cancers, deputy director of Clinical Affairs, assistant dean of translational research, chief of medical oncology, and associate cancer center director of translational science at Yale Cancer Center and Smilow Cancer Hospital, discussed the importance of evaluating ways of altering tumor host factors to improve response to immunotherapy.

OncLive^®: Why does the tumor microenvironment need to be modified for immunotherapy to be effective in some patients, and what approaches under investigation have shown potential?

Herbst: In my presentation I looked at why tumors do not respond to immunotherapy. We know with checkpoint inhibitors, you have to block PD-1 or PD-L1, but that’ll make no difference if you don’t have T cells in the tumor microenvironment. Those T cells need to get to the tumor and interact with the tumor, and sometimes they’re blocked.

In my presentation I provided examples of certain therapies such as Siglec15, which is an antibody against a target that’s involved in immune cell function and thought to work in tumors where PD-L1 is not apparent. I also talked about VEGF inhibition, because vascular endothelial growth factor has a major role in the tumor microenvironment. We’re going to be seeing much more in the next few years about ways to alter T-cell transfer in the microenvironment and break down the barriers to get T cells to the tumors, because if you think about it, more than 50% of lung cancers are cold and have no T cells.

Please elaborate on some of the contributing factors that result in inadequate immunotherapy response.

There’s primary and acquired resistance. Primary resistance would be patients who don’t respond at all. They might not have PD-L1, they might not have T cells in their tumor. And of course, there could be acquired resistance where s[an individual] has activity and then they become resistant as well. In both cases, the microenvironment can play a great role. You’re not going to have PD-1 or PD-L1 upregulated unless you have T cells interacting with the tumor that stimulates interferon, which brings T cells to the tumor. We’ve also found that many tumors are cold and lung cancers are a good example of that. It’s important to have all the components in place. There are so many ways that tumors can be refractory to therapy.

What are some of the methods that have been shown to be effective in improving responses to treatment?

We’re looking for new approaches. One of the best is ramucirumab plus pembrolizumab, which is being evaluated in the phase 2 S1800A trial [NCT03971474] from Lung-MAP. Data were recently presented at the 2022 ASCO Annual Meeting by our team [at Yale]. They showed that adding a VEGF inhibitor in patients who already failed PD-1 or PD-L1 inhibitors resulted in a very nice response. That’s probably the best example out there right now.

Other approaches are looking at VEGF inhibitors whether small molecules or antibodies, and those could be interesting as well. [Another] approach that’s being used is to look at interleukins whether it be IL-2, -10, -15, or -18. These are all approaches that are out there right now, but to my knowledge, none has struck paydirt yet.

What’s next for the field?

Personalized immunotherapy. We have to find ways to understand why the tumor is resistant and target it with the right drug or combinations of drugs. One approach perhaps in tumors that don’t have T cells in the microenvironment might be cell therapy, approaches where you can influence the T cells ex vivo and give them back to a patient.

We’re constantly trying to raise the bar. Immunotherapy has changed the paradigm and outcomes for patients. It’s providing hope for patients with lung cancer, but it’s not enough. The next step is to figure out how to do it even better with combination approaches.

There’s a lot of translational research going on in lung cancer. The most exciting thing to me is that these drugs, especially immunotherapy and targeted therapy are moving to the earliest stages of disease [and] to the adjuvant and the neoadjuvant setting. That’s really going to make a difference: bringing the best drugs or the right targets, right biomarkers to the earliest stage of the disease to cure patients with lung cancer.