These hurdles include finding the right targets, minimizing the risks of the treatment, and reducing the enormous burdens getting these therapies places on patients.
“Precision immunotherapy,” or unleashing the immune system in a highly specific manner, “is obviously, in a way, a holy grail” in lung cancer, said Martin Forster, MD, PhD, who cochaired a session on the topic at the World Conference on Lung Cancer (WCLC) 2024.
He underlined, however, that “immunology is very complex, as is cancer biology,” and consequently, there are different avenues being explored, including CAR T-cell therapies, T-cell receptor therapies, and tumor-infiltrating lymphocytes, among others.
Antibody technology is also being harnessed to target chemotherapy, via antibody-drug conjugates, noted Forster, who is clinical lead of the early phase clinical trials programme at University College London in England.
Moreover, investigators are looking at combining various therapies, such as immune checkpoint inhibitors with T cell–engaging approaches.
He highlighted, however, that the ideal target for these approaches is something that is recognized by the immune system as being foreign, but is found within the cancer, “and you also want it ideally to be in all of the cancer cells.”
A good example is a clonal change, meaning an early evolutionary genetic alteration in the tumor that is present in all the cells, Forster said.
Identifying the Right Target
“One of the big challenges in all forms of targeted immunotherapy is around selecting the target and developing the right product for the right target,” Forster emphasized.
“This concept works really well in hematological malignancies” but is “proving to be more challenging to deliver within solid malignancies,” he added.
“The reason why so many lung tumors are resistant to immunotherapy is because they ‘re immunologically cold,” Roy Herbst, MD, PhD, Department of Medical Oncology, Yale Comprehensive Cancer Center, New Haven, Connecticut, said in an interview.
“There are no T cells in the tumor,” he explained, so it “doesn’t really matter how much you block checkpoint inhibitors, you still have to have a T cell in there in order to have effect.”
To overcome this problem CAR T-cell therapies are engineered to target a tumor, Herbst continued, but that “is a little hard in lung cancer because you need to have a unique antigen that’s on a lung tumor that’s not present on normal cells.”
Charu Aggarwal, MD, MPH, Leslye M. Heisler Associate Professor for Lung Cancer Excellence, Penn Medicine, Philadelphia, Pennsylvania, agreed, saying that there is “a lot of excitement with CAR T-cell therapies, and the promise of cure,” but “the biology is not as simple as we think.”
“For example, it’s not as simple as CD20 or CD19 targeting,” she said in an interview. “Most of the antigens that are being targeted in the solid tumor world, unfortunately, are also expressed on normal tissue. So there is always this potential for toxicity.”