Emergence of Combination Cancer Therapy As New Targeted Approach

Release Date: 20-Oct-2022

In the recent years, cancer has rapidly grown to become one of the most life threatening diseases, taking the lives of millions every year. There are several forms of cancer, both genetic and acquired, which affect people indiscriminately, often imposing an economic burden on them because of the high costs associated with treatment, which go on for a long time. With several recent discoveries and advancements in the facts and figures related to cancer, researchers and scientists have been able to come up with several drugs, therapies and treatment regimens to help patients with cancer and to improve their chances of survival.


As researchers’ and scientists’ understanding of cancer and the mechanisms and pathways involved in supplementing tumor growth has increased, so has their indulgent in the discovery and development of novel therapies. There are several treatment methods in use which revolve around blocking the pathways in the body allowing immune cells to kill cancer cells. The most famous cancer drug which works on this mechanism is Keytruda which has been wearing the crown for long. It blocks interaction between the PD andndash; 1 receptor present on T cells and its ligands which enable immune cells to detect cancer cells, which would have not happened otherwise as the interaction causes the T-cell receptor to get dephosphorylated reducing its proliferation and activity.


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However, as essential evolution is to the survival of a living being, cancer cells evolve too to hide from and dodge the immune system to grow further. They do it by eliminating the ability of their surface antigens from being recognized by the immune cells and the release of detrimental cytokines that form an immunosuppressed environment around them. Hence they are able to successfully evade the immune responses which help in further proliferation and spread of the tumor.


Another mode employed by tumors to support their growth is by resisting the cancer treatment itself. This resistance sometimes develops within weeks of starting the treatment or months or even years later. They are able to achieve this by either adapting to the drug or by acquiring molecular changes that render the drug useless. This phenomenon often results in relapse or recurrence of the cancer which affects a lot of cancer patients post treatment. Hence this has pressurized researchers to find methods to prevent this from happening which has led to the development and administration of techniques other than the conventional methods. One of them which has been emerging lately is the targeted combination cancer therapy, which has gained momentum in the last couple of decades.


The introduction of concept of combination therapy for cancer dates back to 1965. A group of researchers, led by the American oncologist Emil Frei, launched the first-ever combination chemotherapy in pediatric patients with acute leukemia, which had fruitful results and has since changed the oncology therapy landscape. In their experiment, these researchers administered anticancer drugs simultaneously rather than giving them singly, providing scope for the treatment of cancers once considered incurable. Since then, the combination cancer treatment has slowly evolved from the administration of multiple anticancer drugs to the combination of two or more types or treatments such as surgery, radiation and chemotherapy, which has shown good results in patients. Further, in 1970s, combination therapy was found to be more effective in patients suffering from lung cancer than single drugs. It was also found that simultaneous intake of two or more anti - cancer drugs gave better results as compared to sequential chemotherapy, where one chemotherapy drug is given after the other.


There are multiple reasons as to why these treatment methods may rather be given in combinations than alone. Often tumors develop resistance to a single treatment method which does not help in curbing its growth and spread to other parts in the body. Other times, a treatment method may not be efficient in treating the various stages at which cancer cells in a tumor are or may not take into account the tumor heterogeneity, which leads to some tumor cells being able to evade the treatment regimen. Sometimes, the recommended and prescribed method needs assistance from other drug or treatment method to increase its efficacy. The foundation for combination therapy is to use drugs that work by different mechanisms, thereby decreasing the possibility that cancer cells will develop resistance. Thus taking these reasons into account, several combinations of approved drugs and therapies are now being given to patients which have successfully helped in the management of cancer and have also shown evidence in countering cancer relapse.


A very commonly used combination therapy in the treatment of cancer is the combination of chemotherapy and surgery, commonly known as neoadjuvant or adjuvant therapies. Neoadjuvant chemo drugs are delivered before the surgery, to help reduce the size of a tumor or kill cancer cells that have spread. This is helpful in making the surgical removal of tumors easier and also makes unfeasible tumors possible to operate on. On the other hand, adjuvant drugs are delivered after surgery to destroy the remaining cancer cells, thus reducing the chances of cancer relapse because of the cells that have been left behind.


Several of these “combinations”, which have shown positive results in clinical trials, have also received approval from the FDA approval, for instance, the combination of two kinase inhibitors named Braftovi (Encorafenib) and Mektovi (Binimetinib) used in the treatment of metastatic melanoma. Unlike the previously mentioned example, this combination is an illustration of targeted therapy wherein, instead of interfering with the body’s pathways, the two drugs specifically block the activities of the BRAF and the MEK molecules. In melanoma, these two genes are found to be mutated which results in the release of atypical signals from the altered BRAF and MEK proteins. The combination of Braftovi and Mektovi has been shown to block these abnormal signaling pathways, which helps in slowing or stopping the out-of-control cell growth.


In recent years, combination therapies have been gaining popularity because of the successful prevention of drug resistance by cancer cells leading to an increased treatment efficacy and a significant reduction in the duration of the therapy. Simultaneously, targeted therapies, like the one mentioned above, have been getting attention too because they can effectively kill cancer cells without harming the normal cells and hence have a higher success rate with low remission rates. They are also less toxic compared to the standard chemotherapy and are thus preferred by patients and health professional alike.


CAR andndash; T cell therapy is probably the most well - known mode of targeted therapy and its combination with another therapeutic agent such as RNA vaccines and oncolytic viruses are being trialed clinically and have shown successful outcomes. Recently, a Germany based biotechnology company, BioNTech, announced that the combination of its CAR - T candidate BNT211 with an RNA vaccine booster has been given a Priority Medicine (PRIME) status by the European Medicines Agency (EMA) for the treatment of multiple solid tumors showing overexpression of the oncofetal antigen Claudin andndash; 6 (CLDN6). The RNA vaccine helps in promoting the expression of CLDN6 on dendritic cells, which enhances the efficacy of CLDN6 - directed CAR andndash; T cell therapies. This approach was first described by Reinhard and his team and was called the “CARVac” strategy, a two part process to overcome poor CAR andndash;T activity.


Other than targeted therapy and the conventional cancer treatment methods, there are more treatment strategies which have been developed to have stronger detrimental effects on tumor cells. Immunotherapy is one such approach identified by researchers which is now being used in the treatment of cancer and some autoimmune diseases. Other than being a targeted therapy, CAR andndash; T cell therapy is also an immunotherapy which utilizes the body’s T andndash; cells in attacking cancer cells. Moving on from the usage of the combinations developed within the three conventional cancer treatment methods, i.e., radiation, chemotherapy and surgery, they are now instead being combined with the different immunotherapies available in the market. This newer method benefits cancer patients more in the long run than the other combinations mentioned above.


When chemotherapy is used in combination with immunotherapy, the benefits go beyond than just destroying cancer cells. While chemo drugs kill and break down cancer cells, immunotherapy drugs help the immune cells of the body in recognizing the various antigens that are expressed on cancer cells and learning the abnormal pattern demonstrated which can help later during cancer relapse. This phenomenon is called the abscopal effect and is also seen when radiation is combined with immunotherapy. The immune system may then attack these returning cancer cells without external stimulation as they are now trained in recognizing those antigens from the previous chemotherapy andndash; immunotherapy combination treatment.


From these examples, it is evident that combination therapy for cancer has far more benefits than any single therapy and it still has the potential to develop further, given the endless number of combinations that can be construed from the already existing therapies. With the current ongoing research, scientists are also in the process of discovering newer antigens presented by cancer cells and proteins produced by these cells with altered, abnormal genes. This provides even more opportunities to develop targeted therapies, which can be combined with other existing therapies to have a more proficient effect on cancer cells. Combination therapy is already a go - to therapy in cancers like bone and breast cancers, but its applications are now an emerging for other cancer types. This therapeutic segment may potentially hold the key for finding better treatments or perhaps, even cures for cancer, which is the need of the hour considering the ever increasing number of patients getting diagnosed every year.

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