Immunotherapy

Rather than directly killing tumor cells, immunotherapies work by stimulating or suppressing the immune system to help the body fight off cancer, according to the NCI’s definition.3

The idea of immunotherapy was conceived around the 1970s as a natural way of fighting off cancer amid frustration that early chemotherapies failed to meet high expectations of efficacy and entailed severe side effects. Initially, the first ones were cytokines such as interferons and interleukins. “People [were] excited about those, but they [didn’t] deliver as much ‘oomph’ as people expected” at the time, Dr Timmermann said.

Today, the range of immunotherapies includes chimeric antigen receptor (CAR) T-cell (CAR-T) therapies, immune checkpoint inhibitors, as well as immunomodulators, which include cytokines. Although some monoclonal antibodies are called immunotherapies simply by virtue of being antibodies, there’s a distinction between those that target molecules on tumor cells and directly aid in killing them vs immunotherapy antibodies, which work more indirectly “by activating some component of the immune system, which is then killing the tumor,” Dr Mueller explained.


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For instance, the immune checkpoint inhibitors nivolumab (Opdivo®) and pembrolizumab (Keytruda®) are both monoclonal antibodies that target programmed cell death 1 (PD-1), a receptor on T cells and some other immune cells which, when bound to the programmed cell death ligand 1 (PD-L1) protein on other cells, prevents the immune system from attacking those cells. Some tumor cells also express PD-L1, thus preventing the immune cells from attacking them. By blocking PD-1 on immune cells, the monoclonal antibodies are “essentially releasing the brakes on those T cells,” Dr Mueller said. But, “that’s how you end up with all the side effects that are more autoimmune in nature,” she added.

However, the monoclonal antibody rituximab (Rituxan®), which binds to the CD20 surface receptor of B cells, including malignant ones, and acts as a flag for the immune system to destroy those cells, is “a hard one to categorize,” she added in an email. Rituximab is an immunotherapy in the sense that it harnesses the immune system to attack cancer cells, but when treating B-cell malignancies, for instance, it’s targeting cancer cells directly. “So, I guess you could call it targeted since it’s also acting directly on the tumor.”  

There are some therapies where the distinction between being called a “targeted therapy” or an “immunotherapy” is blurry, like for oncolytic viruses, Dr Mueller noted. Talimogene laherparepvec (T-VEC), for instance, is a genetically modified herpes virus that is injected into melanoma tumors and replicates and kills tumor cells — but it also carries a genetic construct encoding a cytokine that boosts the immune response to the tumor. “It’s always categorized as an immunotherapy because it sort of kills the tumor, and then the tumor kind of gets eaten up by the immune system, and that helps activate it. But it’s also targeted in the sense because an oncolytic virus infects tumor cells and kills them,” she said. “That’s kind of a crossover.”

Immunomodulators

The American Cancer Society has no official definition for the term “immunomodulators”. The NCI considers immunomodulators a subgroup of immunotherapies which, broadly speaking, enhance the immune system’s response against cancer cells.4 According to the agency, they include interferons and interleukins, which have a subtler effect than some other immunotherapies. It also includes Bacillus Calmette–Guérin (BCG), a weakened version of the tuberculosis bacterium that elicits an immune response when injected into bladder cancer, and immune-stimulating drugs such as thalidomide (Thalomid®), lenalidomide (Revlimid®), and imiquimod (Zyclara®).

Dr Mueller added that she’d include cancer vaccines in that bucket, and drugs currently in the pipeline that target Toll-like receptors (TLRs) such as TLR7, TLR8, and TLR9. Those aim to activate parts of the less-specific, early-responding innate immune system. “I view them all as drugs that are altering the state of the immune system in the patient,” she said. “But it’s a weird term. And we don’t tend to use it a lot on our site, because it’s not as helpful [or] specific as some terminology.”

However, in practice, when grouping cancer therapies in studies, it often depends on the clinical setting and the precise research question in terms of how different therapies are grouped, Maurer said. For instance, some patients with follicular lymphoma, the most common indolent B-cell lymphoma, receive lenalidomide plus rituximab as upfront therapy, which has been shown to have similar outcomes as certain treatment with immunochemotherapies. “So if I’m analyzing it, I’m probably going to group those patients with the immunochemotherapy, because it’s kind of the same clinical setting, [although] the mechanism of action is slightly different,” Maurer said.

Personalized and Precision Medicine

Many use these terms interchangeably, as the American Cancer Society’s definition of the 2 confirms.5 Yet the NCI defines them slightly differently — “personalized medicine” referring to approaches that use information on a patient’s own genes or proteins to treat their disease, and “precision medicine” for when doctors “select treatments that are most likely to help patients based on a genetic understanding of their disease.”6,7 The term “precision medicine” is more recent and perhaps reflects a recognition that “personalized” medicine can’t be truly personalized, but is rather tailored to a specific subpopulation of patients, Dr Timmermann noted.

The terminology will continue to develop as the therapies themselves do, Maurer noted. “I think it’s going to continue to evolve. . . . So we’ll have to continue to figure out how we’re going to group some of these things.”

References

  1. National Cancer Institute’s Dictionary of Cancer Terms. Targeted therapy. Accessed November 7, 2020.
  2. Timmermann C, Bieri AL, Keller GA. Moonshots at Cancer: The Roche Story. Basel, Switzerland: Editiones Roche; 2020.
  3. National Cancer Institute’s Dictionary of Cancer Terms. Immunotherapy. Accessed November 7, 2020.
  4. National Cancer Institute’s Dictionary of Cancer Terms. Immunomodulating agent. Accessed November 7, 2020.
  5. American Cancer Society. Precision or personalized medicine. Updated April 24, 2020. Accessed November 7, 2020.
  6. National Cancer Institute’s Dictionary of Cancer Terms. Personalized medicine. Accessed November 7, 2020.
  7. National Cancer Institute’s Dictionary of Cancer Terms. Precision medicine. Accessed November 7, 2020.