Steven A. Rosenberg, MD, PhD
Today, the term immunotherapy is ubiquitous in discussions about cancer, but when Steven A. Rosenberg, MD, PhD, and colleagues at the National Cancer Institute (NCI) cured 33-year old Linda Taylor’s metastatic melanoma with infusions of interleukin 2 (IL-2) in 1984, immune-oncology was a nascent field.
The NCI’s early clinical trials of IL-2 helped transform immunotherapy from the theoretical to the practical, and insights gleaned about T-cell responses laid the foundation for an immunotherapy approach known as adoptive cell therapy (ACT). T cell–based ACT uses autologous tumor-infiltrating lymphocytes (TILs) selected for their antitumor reactivity or autologous T cells genetically engineered with T-cell receptors (TCRs) or chimeric antigen receptors (CARs), which are infused back into the patient to induce antitumor effects. An emerging approach to cellular therapy uses natural killer cells engineered with CARs. Overall, these strategies form a major area of research in the evolving immune-oncology field (Figure1
In clinical trials, ACT has shown strong efficacy in blood cancers, and the FDA recently approved 2 anti-CD19 CAR T–cell therapies for certain relapsed B-cell malignancies in adults and children, tisagenlecleucel (Kymriah) and axicabtagene ciloleucel (Yescarta). The success of CAR T cell–therapies in hard-to-treat leukemias and lymphomas led the American Society of Clinical Oncology to designate ACT the Advance of the Year in 2018.
However, achieving consistent success with ACT in solid tumors has proved more elusive. Investigators are exploring a variety of novel strategies to expand the utility of these groundbreaking technologies. These efforts were highlighted during the Society for Immunotherapy of Cancer Annual Meeting (SITC 2018) that took place in Washington, DC, in November. Rosenberg and other experts discussed the challenges of applying ACT to solid tumors and the progress made toward overcoming them in interviews with OncologyLive®
in advance of the conference.
Expectations that such efforts will eventually succeed are high. “I think that not only the American Society of Clinical Oncology, with its 40,000 members, but [also] the oncology field as a whole is looking to ACT for some major improvements for people who have cancers that cannot be successfully treated today,” said Rosenberg, a 2013 Giants of Cancer Care®
Figure. Categories of T-Cell–Based Immuno-Oncology Therapies1
Identifying the Right Targets
Solid tumors present several barriers to ACT efficacy that are largely absent in B-cell malignancies: heterogeneous antigen expression, a hostile immunosuppressive microenvironment, and sites that are difficult for the infused T cells to track to and infiltrate. The range of antigens expressed in solid tumors poses problems for both TIL and CAR T-cell therapies.
Chantale Bernatchez, PhD, a member of the TIL laboratory at The University of Texas MD Anderson Cancer Center in Houston, said the goal of TIL therapy, which uses antitumor reactive TILs isolated from tumor tissue and expanded in the laboratory for reinfusion, is to boost a patient’s preexisting tumor response. The infused TIL populations target multiple tumor epitopes, but “we don’t know what antigens are recognized by the majority of the cells infused,” she said.
Rosenberg and colleagues were the first group to use TIL therapy in metastatic melanoma, one of the most mutagenic cancers.2
After years of refinement, TIL therapy today can achieve complete durable regressions in about 30% of patients with metastatic melanoma. DNA studies of TILs reactive against melanoma have shown that they recognize differentiation antigens, expressed by healthy melanocytes and melanoma; cancer germline antigens, primarily limited to germ and cancer cells; and neoantigens, which are protein fragments found just on the surface of cancer cells.
“Every DNA mutation we target gives rise to a protein that does not exist in normal tissues. Those are called neoantigens because they arise ‘newly’ from mutations in the DNA in that patient’s tumor,” Rosenberg said. Advances in whole exome and RNA sequencing facilitated the identification of neoantigens and opened the door to applying ACT to the common epithelial cancers, which he said caused about 550,000 deaths in the United States in 2018. “Most people think the common cancers are not immunogenic, but… virtually all the epithelial cancers contain mutations that are recognized by the patient’s autologous immune system,” he said.