If your past 20 years were focused on propofol and sevoflurane, you might have missed a scientific revolution that has utterly transformed cancer therapy. It represents one of the great advances in medicine during our lifetimes.
Killing cancer cells without killing the patient has always been a fundamental challenge in chemotherapy. One of the great medical developments of the last century was the discovery that drugs which interfered with mitosis selectively killed cancer cells because of their unconstrained division. In the latter half of the 20th century, chemotherapeutic combinations were discovered that could cure many lymphomas, leukemias, and testicular cancers. These therapies proved less effective against more indolent malignancies. Also, doses were always limited by the need to avoid collateral injury to rapidly dividing normal tissues such as the gastrointestinal and hematopoietic systems.
Cancer cells express unusual proteins on their surface that should activate our immune systems. For years, nobody understood why the immune system stood by passively while cancer cells proliferated and metastasized with impunity. Now we know.
The explanation requires a quick review of why our immune system doesn't attack our own cells. Our T cells have surface receptors finely balanced between “attack” and “stand down.” If a nearby cell has an antigen (e.g., protein) on the surface that binds to an “attack” receptor on the T cell, the T cell attacks. If a nearby cell has an antigen that binds a “stand down” receptor, then the T cell moves along. The “stand down” receptors are called immune checkpoints. Immune checkpoints prevent our immune system from killing everything else. Cancer cells over-express these “stand down” immune checkpoint receptors, telling T cells to just move along.
Immune checkpoint inhibitors are monoclonal antibodies that block the “stand down” response of T cells. Unlike chemotherapy, which kills cancer cells directly, immune checkpoint inhibitors allow the immune system to do its job and kill the malignant cells.
The 2018 Nobel Prize in Medicine and Physiology was awarded to James Allison and Tasuku Honjo “for their discovery of cancer therapy by inhibition of negative immune regulation” (asamonitor.pub/3c6wiIn). Allison was awarded the prize for his discovery of cytotoxic T-lymphocyte antigen-4 (CTLA-4), while Honjo was recognized for the discovery of programmed death molecule 1 (PD-1) (Biomed J 2019;42:299-306).
The tumor microenvironment
The tumor microenvironment is “a highly heterogeneous milieu consisting of different cell types and many abundant molecules produced and released by tumor cells, stromal cells, and immune cells” (Front Immunol 2020;11:940). The immune response is a complex interaction among CD4+ (helper) T cells, CD8+ (cytotoxic) T cells, natural killer (NK) T cells, regulatory T cells (Tregs), myeloid-derived suppressor cells, and tumor-associated macrophages.
T cells are activated to attack foreign cells through a rather formal process. An unrecognized antigen is presented to the T cell by an “antigen presenting cell,” a process not unlike presenting a handkerchief to a bloodhound (“Go find this!”). The newly activated T cell needs to be throttled back, lest it go on a rampage. The antigen presenting cell does this by binding the CTLA-4 receptor on the T cell (Figure 1). This receptor inhibits cytotoxicity (Cancer Discov 2018;8:1069-86). However, if CTLA-4 is somehow blocked, it “release{s} the brake on the immune system.” The now disinhibited T cell avidly hunts down its target, which is hopefully the cancer cell. Cancer cells try to bind to CTLA-4, but the receptor is blocked by the antibody. The first monoclonal antibody against CTLA-4 was ipilimumab, which was approved by the FDA in March 2011 for the treatment of late-stage or metastatic melanoma (asamonitor.pub/3PmaZRl).
Figure 1 shows how CTLA-4 interacts with antigen presenting cells to deactivate T cells. If CTLA-4 is blocked, the T cell is activated.
Figure 1 shows how CTLA-4 interacts with antigen presenting cells to deactivate T cells. If CTLA-4 is blocked, the T cell is activated.
“Cancer cells express unusual proteins on their surface that should activate our immune systems. For years, nobody understood why the immune system stood by passively while cancer cells proliferated and metastasized with impunity. Now we know.”
The second immune checkpoint identified as a drug target was the attractively named “programmed death 1,” or PD-1, receptor on the T cell. (Figure 2). PD-1 binds to a ligand on the nearby cancer cell, PD-L1 (EMBO J 1992;11:3887-95). B cells and T cells both express PD-1 when activated (Int Immunol 1996;8:765-72). When PD-1 on the T cell binds PD-L1 on the nearby cancer cell, the T cell stands down, creating “a negative feedback loop to attenuate local T cell responses and minimize tissue damage” (asamonitor.pub/3PmaZRl). Immune checkpoint inhibitors prevent this by binding PD-1 on the T cell side, or PD-L1 on the cancer cell side. Either way, the result is to unleash the T cell so it can kill the cancer cell. Pembrolizumab, nivolumab, and cemiplimab are approved monoclonal antibodies against PD-1. Pembrolizumab and nivolumab received regulatory approval from the FDA for the treatment of advanced melanoma in September 2014 and December 2014, respectively (asamonitor.pub/3o3vcQc; asamonitor.pub/3yYLsIO). Atezolizumab, avelumab, and durvalumab are approved monoclonal antibodies against PD-L1.
Figure 2 shows how PD-1 and PD-L1 interact with the tumor cell. If PD-1 binds to PD-L1, the T cell is inactivated. If the binding is blocked by antibodies to PD-1 or PD-L1, then the T cell is activated.
Figure 2 shows how PD-1 and PD-L1 interact with the tumor cell. If PD-1 binds to PD-L1, the T cell is inactivated. If the binding is blocked by antibodies to PD-1 or PD-L1, then the T cell is activated.
To increase efficacy and prevent cancers from becoming resistant to immune checkpoint inhibitors, CTLA-4 and PD-1 targeting antibodies (e.g., ipilimumab plus nivolumab) are often given in combination. Immune checkpoint inhibition is often combined with standard chemotherapies. The next step in this revolution is the combination of immune checkpoint inhibition with cytotoxic drugs linked to antibodies that target proteins on the surface of cancer cells. These antibody-linked chemotherapeutic drugs deliver their deadly payload directly to the tumor (Cancer Treat Rev 2022;106:102395).
Discussion
As summarized in a recent review in Nature Communications, “immunotherapy using immune-checkpoint modulators revolutionizes the oncology field far beyond their remarkable clinical efficacy in some patients. It creates radical changes in the evaluation of treatment efficacy and toxicity with a more holistic vision of the patient with cancer” (Nat Commun 2020;11:3801). Lewis and colleagues recently published an excellent review of the anesthetic implications of immunotherapies (Br J Anaesth 2020;124:251-60).
The authors have seen previously untreatable tumors melt away in friends and colleagues. Similar results have been reported in clinical trials, including a recent headline-grabbing paper in the New England Journal of Medicine documenting complete tumor disappearance in 12 patients with locally advanced rectal cancer treated with dostarlimab, an anti-PD-1 monoclonal antibody (N Engl J Med 2022 Jun 23;386:2363-76). Twelve patients may be a small sample, but complete disappearance of advanced colorectal cancer is unheard of.
We still do not know whether the response to immunotherapy is durable. We don't know how quickly cancers can evolve escape mechanisms. We don't know the optimum combination of immune checkpoint inhibition, immune targeted chemotherapy, radiotherapy, and surgery to treat most cancers. There is much that we do not know, but we do know this is a revolution in cancer therapy.
Richard Simoneaux is a freelance writer with an MS in organic chemistry from Indiana University. He has more than 15 years of experience covering the pharmaceutical industry and an additional seven years as a laboratory-based medicinal chemist.
