A 72-year-old Connecticut citizen Bob Carlson was diagnosed with lung cancer four years ago. The doctor estimates that he will not live longer than two years. He tried a variety of programs and repeatedly failed. That makes the old man almost lose his courage until he participated in a clinical trial at the Yale Cancer Hospital and began to receive immunotherapy treatment from Roche, a Swiss pharmaceutical company.
“I said goodbye to all my friends and relatives, but two years have passed and I still survive.”
No one was more surprised by the therapeutic effect than Carlson. Lung tumors began to shrink at the beginning of treatment. He did not have to experience the side effects of chemotherapy or the painful of surgery. This is the cover story of Barron’s magazine in August 2015. The technology of immunotherapy, which has been quiet for nearly a century, has finally ushered in its spring. It shows hopeful tomorrow and hope with one miracle case after another.
Immunotherapy is rapidly advancing and can now be considered to be the “fifth pillar” of cancer therapy, joining the ranks of surgery, cytotoxic chemotherapy, radiation, and targeted therapy. The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period, with multiple anecdotal reports of tumors miraculously disappearing, sometimes spontaneously or after a febrile or infectious episode. Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon. Why does it happen? it is recognized that immunosuppression is associated with a higher cancer risk. That is to say, once the immunosuppression state was relieved, the patient’s own immune system is capable of killing and eliminating tumor cells by itself.
Immunotherapy is a treatment that uses certain parts of a person’s own immune system to fight diseases such as cancer. This can be done in a couple of ways:
- Stimulating your own immune system to work harder or smarter to attack cancer cells;
- Giving you extra supplementary immune components, such as man-made immune system proteins.
Immunotherapy includes treatments that work in different ways. Some boost the body’s immune system in a very general way. Others help train the immune system to attack cancer cells specifically. During the long course of evolution, cancer immunotherapy has also spawned different branches, broadly divided into four major categories: nonspecific immunostimulants & suppressant, tumor vaccines, adoptive cell therapy, and immune checkpoint inhibitors.
Non-specific immunostimulants/suppressant
Non-specific immunostimulants/suppressant do not specifically target tumor cells, but rather have a better effect on cancer by up/down-regulating the body’s immune function. As the earliest cancer immunotherapy, non-specific immune enhancers were applied clinically as early as the 1990s. The most common non-specific immunostimulants include interleukins and interferons. Because the human immune system plays a role in identifying the “enemy” function, non-specific upregulation of its function will often result in friendly fire to the body and thus produce more serious side effects such as flu-like symptoms, rash, leukopenia, etc., so the usage of non-specific immunostimulants has been limited, more often as an adjunctive use in combination with other immunotherapy or chemotherapy.
Tumor vaccine
Researchers are using both of the two kinds of vaccines to treat or prevent tumor development. Preventive vaccines are those that can prevent certain types of cancer before tumors develop, while therapeutic vaccines are those that activate immune cells with disease-fighting agents. At present, there are four types of vaccines approved by the FDA for cancer treatment. They are Gardasil (product of Merck) and Cervarix (products of GSK) for the prevention of cervical cancer, hepatitis B vaccine for the prevention of liver cancer, and Provenge for the treatment of advanced prostate cancer. Human papillomavirus HPV is considered to be a cause of cervical cancer of more than 90% of patients, and highly pathogenic 16, 18, 31, 33, 45, 52, 58 subtypes can be prevented by inoculation of a 9-valent HPV vaccine. Similarly, more than 90% of primary liver cancer patients are HBsAg-positive hepatitis B patients, the probability of developing liver cancer can be greatly reduced by vaccination with hepatitis B vaccine. Unlike preventive vaccines that prevent cancer from occurring through the prevention of cancer-associated viral infections, the therapeutic cancer vaccine Provenge is the first truly cancer vaccine. The vaccine developed by Dendreon Co., Ltd. was used to isolate dendritic cells from patients and co-cultured in vitro with prostatic acid phosphatase (PAP), which is highly expressed in prostate cancer cells. The dendritic cells learned to recognize this specific antigen. After being adapted back to the patient, the dendritic cells process the PAP antigen and present it to the T cells surface. The latter finds prostate cancer cells expressing PAP in the body and kills them.
Adoptive cell therapy
Adoptive cell therapy (ACT) is another type of immunotherapy which mostly involves the isolation, gene modification and in-vitro expansion of tumor-specific T-cells, followed by infusion back into the cancer patient. These efforts have also extended to using natural killer cells, since they display rapid and potent immunity to solid tumor metastasis and hematological cancers. There are many forms of ACT, including those using techniques such as culturing tumor-infiltrating lymphocytes (TIL) obtained directly from the tumor; isolating and expanding one particular T-cell or clone with high affinity TCRs (TCR-T); or using T-cells that have been engineered in vitro to potently recognize and attack tumors, which technique is known as chimeric antigen receptor T-cell (CAR T-cell) therapy. Although ACT has produced remarkable results in clinical trials with melanoma and hematologic malignancies as well as with solid cancers, some deaths have occurred in the trial phases secondary to marked cytokine release (“cytokine storm”, or “cytokine release syndrome”) and cerebral edema.
Immune checkpoint inhibitor
In order to ensure that an immune inflammatory response is not constantly activated once foreign or tumor antigens have stimulated a response, multiple controls or “checkpoints” are in place or activated. Immune checkpoints are regulators of the immune system. These pathways are crucial for self-tolerance, which prevents the immune system from attacking cells indiscriminately. These checkpoints are mostly represented by T-cell receptor binding to ligands on cells in the surrounding microenvironment, forming immunological synapses which then regulate the functions of the T-cell, which become specialized, or “polarized”, to perform different activities. Immune checkpoint inhibitors basically take the ‘brakes’ off the immune system, which helps it recognize and attack cancer cells. More than twenty checkpoint molecule pairs, both costimulatory and co-inhibitory, have been discovered, including TIGIT/CD155, LAG-3/MHCII, and TIM3/Gal- 9, which are variably expressed not only by T-cells but also by other cells of both myeloid and lymphoid derivation. The two pairs of inhibitory receptor/ligands which have received the most attention in recent years are cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) receptor with B7 ligand, and programmed cell death protein 1 (PD1) receptor with PD1-L1 ligand. CTLA- 4 has very high homology to CD28, with a higher competitive binding affinity to B7, causing inhibition of proliferation and IL-2 secretion by T-cells. Unlike CTLA-4, PD-1 does not interfere with costimulation, but generates signals that prevent phosphorylation of key signaling intermediates in the T-cell, which reduces their activation. Ipilimumab (Yervoy) is a monoclonal antibody that attaches to CTLA-4 and stops it from working. This can boost the body’s immune response against cancer cells. This drug is used to treat melanoma of the skin. It is also being studied for use against other cancers. Because ipilimumab affects the immune system, it can sometimes cause serious or even life-threatening side effects. There are more PD-1 and PDL-1 inhibitors, such as Pembrolizumab (Keytruda) and Nivolumab (Opdivo) as PD-1 inhibitors, and Atezolizumab (Tecentriq), Avelumab (Bavencio), Durvalumab (Imfinzi) as PDL-1 inhibitors. These inhibitors have been shown to be effective in treating melanoma of the skin, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, and Hodgkin lymphoma. Common side effects of these drugs can include fatigue, cough, nausea, loss of appetite, skin rash, and itching. Less often they can cause more serious problems in the lungs, intestines, liver, kidneys, hormone-making glands, or other organs.
Oncolytic virus therapy
Oncolytic virus immunotherapy represents a novel form of cancer therapy that employs native or engineered viruses that selectively replicate in and kill cancer cells. OVs are believed to promote antitumor responses mainly through two distinct mechanisms of action: acute tumor debulking owing to tumor cell infection and lysis, and induction/initiation of systemic antitumor immunity. Many of the “hallmarks of cancer”, such as sustained proliferation, usurping cellular apoptotic programs, and inactivating growth suppressors favor the selective replication of OVs in malignant cells with minimal toxicity to normal tissues. The viral genome can be modified to augment antitumor activity and attenuate pathogenicity. Additionally, OVs can be engineered to express specific cytokines that favor immune cell recruitment and activation or to produce T cell co-stimulatory molecules on infected tumor cells, thus facilitating the generation of T cell activating signals. the most advanced agent in clinical development is Talimogene laherparepvec (T-VEC), which has recently been approved by the FDA for the treatment of advanced melanoma. Although promising, there are limitations associated with oncolytic therapy. OV-mediated antitumor immunity could be compromised in those immunocompromised patients. The fact that OVs are injected locally into the tumor to avoid pre-existing antiviral immunity is also considered a limitation because, in this case, the virus may not reach tumors in organs that are difficult to reach with an injection
Cancer therapy has long depended on strategies that directly attack tumor cells to treat patients. Cancer immunotherapy, the treatment that harnesses the patient’s immune system to fight cancer, is now emerging as an important addition to conventional therapies. Immunotherapies do not yet represent a panacea in cancer therapy since only a minor subset of some cancers respond to some of these treatments, and it is difficult or impossible to determine precisely who will benefit. However, with the continuous development of modern immunology, scientists will have a deeper understanding of the mechanism of tumor immunity. We believe that in the near future, we will have the opportunity to fully understand the means of regulating the immune system so that immunotherapy can become more reliable and predictable.