For the first time ever, a new drug was able to completely eliminate cancer in every patient in a clinical trial without causing any adverse side effects1,2. It caused some to claim that finally there might be a cure for cancer3. Actually, cancer is not just one disease – it is many diseases. Moreover, the patients were selected because they had a rare form of rectal cancer (DNA mismatch repair deficiency) that is seen in only 5–10 percent of rectal cancer patients.
Patients with such tumors tend to be less responsive to chemotherapy and radiation treatments, which increases the need for surgical removal of their tumors. Ordinarily, patients with these kinds of rectal tumors might expect to undergo chemotherapy and radiation therapy prior to surgical removal of cancer. They can suffer from bowel and bladder dysfunction, incontinence, infertility, sexual dysfunction, and more. The patients in this study have so far completely avoided both these procedures and their associated side effects. However, DNA mutations that cause mismatch repair deficiency can make cancer cells more vulnerable to immune response, especially when it's improved by a checkpoint inhibitor. So, the experimental drug Dostarlimab (sold under the name Jemperli) might be a cure for a special form of rectal cancer, but it has been less successful in curing other types of cancer4,5. Still, this new drug is important in the field of immunotherapy, in which one’s own immune system is used to cure different types of cancer6-9.
A healthy immune system can prevent cancer, especially when it is supported by a healthy gut microbiome that comes from consuming dietary fiber and avoiding meat10,11. The ways that a healthy immune system support human health were described in a previous article in this journal12. Immune cells made in the thymus gland (T cells) can recognize cancer cells as being non-self and trigger an appropriate response that eliminates them before they can grow and metastasize. The immune system surveys the body, finds cancer cells and targets them for destruction. This is called immunosurveillance. Tumors are edited by the immune system, but resistant some variants avoid this, due to insufficient immunosurveillance. So, researchers looked for ways to improve the immune system. One of the first immunotherapy successes was in treating metastatic cutaneous melanoma with a protein called interleukin was approved by the FDA in 1998 for treatment of stage IV melanoma with IL-2 to stimulate white blood cell proliferation. However, only a 19% overall response rate was observed, with only a 4% complete response rate, limiting the use of this strategy. However, some cancer cells develop the ability to express a specific protein on their surface that causes the immune cells to die. This protein is called programmed death 1, or PD-1. Research on cancer immunotherapy aims to overcome the ability of cancer cells to resist the immune responses and to stimulate the body's own mechanisms that enable it to remain effective against cancer13,14.
There is a PD-1 receptor on the surface of activated T cells15. It is an immune checkpoint inhibitor that mediates immunosuppression. It is an important part of our natural protection against cancer through a cancer immunity cycle. This cycle enables the immune system to have an anti-cancer response and kill cancer cells. First, dendritic cells capture tumor cells that have mutated cell surface antigens. Second, the dendritic cells prime T cells with the tumor antigen, thus activating cytotoxic T cells. Third, the activated T cells travel to the tumor and infiltrate its environment. Fourth, the activated T cells recognize and bind to the cancer cells. Fifth, the bound effector T cells release cytotoxins that induce programmed cell death (apoptosis) in the cancer cells that they target. Finally, dying cancer cells release more tumor-associated antigens which propagate the immunity cycle further and kill more cancer cells. However, this response must be properly regulated to maintain the balance between appropriate recognition and destruction of tumors and the inappropriate overstimulation of immune responses, that can lead to damage to normal, healthy cells and tissues. The PD-1 (or PD-L1) signaling pathway is an essential part of this regulation.
There are two proteins that can bind to the PD-1 receptor. When one protein binds to another, it is called a ligand. So, biochemists call them PD-L1 and PD-L215. They are widely expressed on the surface of dendritic cells and macrophages in the immune system. PD-L1 and PD-L2 are immune checkpoint proteins that act as co-inhibitory factors. They can halt or limit the development of the T cell response. The interaction between PD-L1 and PD-L2 with their cognate receptor ensures that the immune system is activated only at the appropriate times. This minimizes the probability of chronic autoimmune inflammation. However, tumor cells can exploit this immune-checkpoint pathway, evade detection and inhibit the immune response. The PD-L1 is frequently over-expressed on tumor cells or on non-transformed cells in the tumor microenvironment. PD-L1 on tumor cells can bind to PD-1 receptors on the activated T cells. This inhibits the cytotoxic T cells. These deactivated T cells remain inhibited in the tumor microenvironment.
Perhaps the best-known patient to be successfully treated by blocking PD-1 is President Jimmy Carter, who had metastatic melanoma and received pembrolizumab (Keytruda®)16. In 2015 it was announced that his cancer was in remission. Now, he is 97 years old, healthy and active.
There are other types of immunotherapies that have been somewhat successful. For example, scientists and doctors have eliminated leukemia in several patients by converting their cytotoxic T cells into specific killers of cancer cells17. They used a lentiviral vector to express chimeric antigen receptors (CARs) in patients’ cytotoxic T cells. The gene for the CAR was delivered by a lentivirus vector, which was made by using the backbone of the HIV-1 virus that was no longer pathogenic and couldn’t cause AIDS. Because the natural host for HIV-1 is the T-lymphocyte, the lentivirus vector specifically targeted the cancer cells and multiplied in them. The patients received between 15 million and one billion cytotoxic T-lymphocytes.
Once tumor antigens are identified, active and passive immunotherapies can be devised18. Active immunotherapies induce a tumor-directed immune response by vaccinating patients with tumor antigens. Passive immunotherapies can use cytokines like IL-2, monoclonal antibodies (mAbs) and/or adoptive T cells to stimulate the immune system. There is also a checkpoint inhibitor called CTLA-4 that prevents the activation of T cells. Ipilimumab is a human mAb that blocks CTLA-4, so it is called an immune checkpoint inhibitor. The FDA approved Ipilimumab in 2011 for the treatment of patients with metastatic melanoma. The Nobel Prize in Physiology or Medicine in 2018 was awarded to Professors James Allison and Tasuku Honjo for their research on CTLA-4 and PD-1, respectively.
Passive immunotherapy can also use adoptive T cell therapy (ACT), in which patients are treated with tumor-reactive T cells that are selected and expanded ex vivo18. Both effector and memory T cells can induce complete remission in patients that can’t be cured by other anticancer therapies. The two major sources of T lymphocytes for ACT are the tumor itself and the peripheral blood of the patient. When a tumor is infiltrated by anti-tumor T cells, these cells can be isolated from the resected tumor mass. For example, tumor-infiltrating lymphocytes were isolated from 93 metastatic melanoma patients who had failed chemotherapy and other immunotherapies such as IL-2 and anti-CTLA-4 treatments. The T cells isolated from the resected tumor were first selected for anti-tumor reactivity and then expanded. Twenty patients (22%) achieved a complete regression with ongoing complete responses in 19 of them after three years.
Also, T cells can be modified by CARs18. Unlike T cell receptors that are specific for a complex between human leukocyte antigens (HLAs) and peptides, CARs can recognize antigens without depending on them. This may make CARs useful for patients with different HLA haplotypes, and increase the number of potential targets, including carbohydrates and glycolipids. Although one of the first successful CAR therapies with complete remissions was reported on solid neuroblastoma, they may also be effective against hematological malignancies. The most investigated CAR target is CD19, which is expressed on normal B cells as well as on most B cells in leukemia and lymphomas. Several clinical studies on patients with B cell malignancies (such as CLL) caused partial and complete responses in subsets of patients.
Also, two children with relapsed and refractory acute lymphoblastic leukemia were treated successfully with CARs that targeted CD19. One child was reported to have an ongoing complete regression, while the other one relapsed due to the growth of blast cells that no longer expressed CD19. Still, CD19 CARs killed aggressive leukemia cells. So, T cells with CARs against other targets in combination with CD19 CARs may be useful on tumors that downregulate the CD19 CAR target. Based on the success of CAR therapies in hematological malignancies, the expansion of this therapy to solid tumors may be possible. However, it will be more challenging due to the immunosuppressive tumor microenvironment that can make cell-based immunotherapy ineffective18.
Despite this, an FDA panel recommended the approval of CAR-T gene therapy (Tisagenlecleucel-T, Kymriah®) on 14 July, 2017 for pediatric and young adult patients with B-cell acute lymphoblastic leukemia and it was approved on 30 August19. The extracellular portion of the CAR protein has an antibody fragment that targets CD19. The intracellular portion contains T-cell signaling and co-stimulatory domains that activate T-cells and enable them to persist while exerting anti-tumor activity. Once the CAR protein binds to the CD19 target, the intracellular domains promote the T-cell expansion, while triggering subsequent effector functions that eliminate the targeted B-cells, which are malignant. So, blood cells are removed from the patient at an appropriate medical center and shipped to the manufacturer (Novartis) for processing. Then, they are sent back to the medical center and administered to the patient.
So, there are many types of immunotherapy that are used to treat and possibly cure some types of cancer. Much research is also being done to develop vaccines that can prevent cancer. The same technology that made two very successful Covid-19 vaccines (BNT162b2 by Pfizer/BioNTech and mRNA-1273 by Moderna/Lonza)20.
1 Dockrill, P. Every single patient in this small experimental drug trial saw their cancer disappear. Science Alert, 6 June, 2022.
2 Cercek, A. et al. PD-1 blockade in mismatch repair–deficient, locally advanced rectal cancer . New England Journal of Medicine, 5 June, 2022.
3 Mukhopadhyay, S. Cancer cure finally here? New drug Dostarlimab cures all patients in trial ‘first time in history’. Mint, 8 June, 2022.
4 Oaknin, A. et al. Clinical activity and safety of the anti–Programmed Death 1 monoclonal antibody Dostarlimab for patients with recurrent or advanced mismatch repair–deficient endometrial cancer. JAMA Oncology, volume 6, p. 1766-1772, 2020.
5 Andre, T. et al. Safety and efficacy of anti-PD-1 antibody dostarlimab in patients (pts) with mismatch repair deficient (dMMR) GI cancers. Journal of Clinical Oncology, Volume 38, no. 4_suppl, p. 218-218. 1 Feb., 2020.
6 Pisibon, C. et al. Immune checkpoints in cancers: from signaling to the clinic. Cancers, volume 13, article 4573, 2021.
7 Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, Volume 12, 252-264, 2012.
8 Sgambato, A. et al. Anti PD-1 and PDL-1 immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC): A review on toxicity profile and its management. Current Drug Safety, Volume 11, p. 62-68, 2016.
9 Topalian, S.L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New England Journal of Medicine, Volume 366, p. 2443-2454, 2012.
10 Smith, R.E. Dietary fiber, the gut microbiome and health. There is an undeniable link between the brain, the gut and the immune system. Meer, April 24, 2020.
11 Smith, R.E. Switching to plant-based diet from animal-based diet. Continuously improving dietary guidelines. Meer, Sept. 24, 2019.
12 Smith, R.E. Covid-19: Immune response to the SARS-CoV-2 virus. The response to this virus depends in large part on the health of one’s neuroendocrine immune system. Meer, 24 April, 2021.
13 Sgambato, A. et al. Anti PD-1 and PDL-1 immunotherapy in the treatment of advanced non-small cell lung cancer (NSCLC): A review on toxicity profile and its management. Current Drug Safety, Volume 11, p. 62-68, 2016.
14 Pardoll, D.M. The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews Cancer, Volume 12, 252-264, 2012.
15 Topalian, S.L. et al. Safety, activity, and immune correlates of anti–PD-1 antibody in cancer. New England Journal of Medicine, Volume 366, p. 2443-2454, 2012.
16 Cancer Research Institute, Jimmy Carter’s cancer immunotherapy story. 2022.
17 Radic M. Armed and accurate: engineering cytotoxic T cells for eradication of leukemia. BMC Biotechnology, Volume 12, p. 1-4, 2012.
18 Wayteck L. et al. A personalized view on cancer immunotherapy. Cancer Letters, Volume 352, p. 113-125, 2013.
19 U.S. FDA. Tisagenlecleucel, FDA Briefing Document, 2017.
20 Smith, R.E. Vaccines based on modern RNA technology. This technology's potential for vaccines and other diseases. Meer, 24 December, 2020.