Thursday, December 08, 2022

Bacteria and humans are very different from each other. Therefore, it is relatively simple to find metabolic differences between the two species that can be taken advantage of to develop drugs that can effectively kill one with great efficiency while leaving the other without much in the way of side effects—hence antibiotics. In contrast, normal cells and malignanT-cells are very similar to each other in most ways and so it has been difficult to devise drugs that would kill one with 100% efficacy while not simultaneously harming the other.

Conventional chemotherapy took advantage of differences in growth rates between the two—hence most of the common chemotherapy drugs are proliferation poisons and cause toxicity in normal proliferating cells—the bone marrow and the gastrointestinal tract. Other types of systemic therapy have included hormonal agents for breast or prostate cancer, or antibodies against genetic abnormalities, such as Herceptin for HER2 or Gleevec (imatinib) for c-kit. Of course, this is a very simplistic incomplete list but just to give a flavor of approaches to cancer treatment.

Another longtime goal in cancer therapy has been to bring to bear the immune system to treat cancer. Many approaches have been attempted over the years, some more successful than others, but the one that has become most prominent in recent years and is referred to nowadays when the term “immunotherapy” is used is the use of checkpoint inhibitors. In essence, it involves the mechanism by which T-cells, a type of lymphocyte, recognize cells as self or “other.” There are proteins on the surfaces of normal cells that shut off the immune cells so that they do not react to the normal cells and harm them. While malignanT-cells should not have such safeguards and should be rejected by the immune system and destroyed, it was discovered that most cancer cells do express these checkpoint inhibitor proteins and thereby protect themselves against the destructive effects of the T-cells. Examples of such proteins are PD-1 (programmed cell death protein 1); PD-L1 (programmed death-ligand 1); and CTLA4. These proteins can bind to proteins on the surface of T-cells and cause the T-cell to shut off its immune response to the cancer cell.

James Allison is an immunologist who earned his PhD at the University of Texas-Austin. He has been on the faculty at various institutions, including Scripps, Berkeley, Memorial Sloan Kettering Cancer Center, and now MD Anderson Cancer Center. He discovered that it was the binding of the protein to the T-cell receptor that prevented the T-cells from attacking the cancer cells. He later discovered the T-cell receptor. Allison went on to show that an antibody could be developed that would block the inhibitory molecule on the cancer cell and thereby lead to an increased anti-tumor response by the T-cell and rejection of the cancer cell. The first protein that he did this for was CTLA4 with the antibody ipilimumab (Yervoy).

Tasuku Honjo is a Japanese immunologist at Kyoto University who was working in parallel to Allison. He discovered the PD-1 protein on T-cells and later appreciated that the PD-L1 protein interacted with PD-1. He understood early as well that inhibition of PD-1 was likely to lead to a successful inhibition of cancer cells and treatment of cancer. Drugs that have successfully targeted that PD-1 pathway are nivolumab (Opdivo) and pembrolizumab (Keytruda). Likewise, drugs for the PD-L1 protein include atezolizumab (Tecentriq) and durvalumab (Imfinzi).

This form of treatment has not proved to be universally useful. Its most dramatic benefit has been in the setting of metastatic melanoma, which previously was generally untreatable and almost universally fatal. Now, with immunotherapy, many patients with metastatic melanoma may live years and the cure rate approaches 50%. Significant beneficial results are also seen in many patients with non-small cell lung cancer who can often be treated with immunotherapy as well. There are also subgroups of patients with colorectal or gastric cancer who can benefit from immunotherapy as well for whom extended survival is also possible.

Another advantage of immunotherapy is that the toxicities are relatively less severe than for conventional chemotherapy. It is not nontoxic—just less severe. Hypothyroidism is a significant problem, as is colitis. There are other problems as well, such as rashes and pneumonitis. These classes of drugs are also very expensive, so that needs to be weighed in their use.

Nonetheless, this has been a major step forward in cancer therapy, and the uses and the optimal combinations with standard chemotherapy are still being worked out.

Allison and Tanaka shared the 2018 Nobel Prize in Medicine for their contributions in this area.

Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York.

This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.

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