Cancer Immunotherapy and COVID-19: Mind the Gap

“Mind the gap” is as an audible or visual warning phrase to subway passengers in London of the significant space between the train door and station platform. We utilized this phrase to caution people to be mindful of the significant gap in knowledge about COVID-19 treatment and Cancer Immunotherapy. From the end 2019, a novel coronavirus causing respiratory-related disease known as COVID-19 has spreading rapidly among the whole world. The number of infected persons increasing rapidly worldwide and still continuing. Since the scientific knowledge gained from research on our body immune system and its reaction against foreign particles, it might be helpful to make prevention of future outbreaks. The immunotherapy and research specially help to understand the mechanism of action of virus and other foreign particle in human body and its prevention. On the other hand, cancer immunotherapy is now rapidly growing because of its mechanism is more target specific than chemotherapy or radiation treatment. Moreover, the immunotherapy has less side effects that chemotherapy and radiation commonly have i.e. damage healthy cells, commonly leading to hair loss. The main concern now Abstract


Introduction
a days whether anti-cancer immunotherapy can be used to treat COVID-19 or not? Basically, immunotherapy works on specific cancer immune system not all over the immune system. Sometimes immunotherapy leads to side effects due to its general immune system activation. Currently some immunotherapy used live pathogen to treat cancer [1][2] but these treatments only shown impact on a limited number of patients and cancer types. So, it is important to understand the fundamental differences between cancer immunotherapy and Immunotherapy to treat COVID-19 for the prevention of pandemic. There is an urgent need where Immuno-Oncology can help to make strategies to treat COVID- 19. In this review we present a comprehensive analysis of available information on the drugs which used to treat cancer that can also being use for COVID-19 treatment to shortened the time length during the current outbreak.

Viral vaccines that using to treat Cancer
Seasonal influenza virus infection is the most common viral infection by which people suffer every year. The Centers for Disease Control and Prevention (CDC) mention that, the patients admitted hospital with respiratory illness most of them suffer from influenza-like illness [3].
As per the report, in USA approximately 5%-20% of people infected by influenza virus in each season [4][5]. As per CDC 2019-2020 estimation (www.cdc.gov) 740000 was hospitalized due to flu where near about 64000 died due to this virus [6]. In their article mentioned many other counties estimation on influenza vaccine. To prevent the seasonal flu there is a huge demand in FDA-approved seasonal flu shots. Research is now focus to understand how immune responses against pathogens like influenza and their components could improve our much weaker immune response against some tumor. However, there are many factors involve in live infections, which done not found in tumors. It was found that, direct injection of flu vaccine into the skin melanoma caused the tumors grow slower [7] by increasing immune-stimulating dendritic cells in the tumor, resulting an increase in CD8+ T-cells, which recognize and kill cancer cells. Human dendritic cells (DCs) play a crucial role in the immunity during vaccination against influenza. It was well known that Influenza vaccines trigger immunity through induce an IFN response in DCs, which help to increase the vaccine efficiency [8].There is evidence of clinical trial [9] which proves dendritic cells vaccine (DCV) has minimal toxicity in patients with metastatic melanoma and its gives long time survival benefit. In this regard there is a major question arise that, can a Flu Shot be use full to treat Cancer? According to a publication in Proceedings of the National Academy of Sciences (PNAS), the patients receiving seasonal influenza vaccination may experience multiple clinical benefits like cancer immunotherapy. In a mouse model study, virus-specific memory T cells shows an alarming effect to reduce the tumor growth not only in lung tumour but also in metastatic triple-negative breast cancer [10]. Recently a study published where it was shows that flu vaccine is safe and dose not exacerbates immune events in cancer patients treated with immune checkpoint inhibitors (ICIs). However another study that contain 162 patients, showing no impact in response to flu vaccines in patients receiving checkpoint inhibitors [11]. Since the flu shots has been used by millions of people and have already proved its safe, so research start to use flu shots to treat cancer but to start application largely its need more clinical trial outcome. Since, combination therapies are current frontline therapies for cancer, researcher start to use Influenza vaccines combined with cancer immunotherapy.
There are several targets of vaccine that is under evaluation in clinical trials which are-CEA, Cytomegalovirus (CMV)-related antigens: foreign viral proteins expressed by CMV-infected cancer cells; Folate-related proteins; EGFR; HER2;Human Papilloma Virus (HPV)-related antigens; MAGE antigens; Mesothelin; MUC-1;NY-ESO-1;P53; PAP and PSA, Personalized neoantigens; Ras; Survivin; WT1. Most significant FDA-approved vaccines that are used for cancer immunotherapy are listed in Table 1 [12]. In their article describe in detail about therapeutic cancer vaccine and its future platform. Future directions are needed to involve the viral-based vaccines to treat patients regards adjuvant and neo-adjuvant settings and in combination with immunotherapy. An appropriate clinical endpoint is needed for therapeutic vaccines which will define the main strategies for the combination immunotherapy for cancer treatment.

Cancer vaccine to Treat Covid-19
Since SARS-CoV-2 coronavirus that causes the respiratory-related disease known as COVID-19 has spread widowed manner, researchers are working on preventive vaccines in an urgent basis. Based on the results of annual flu vaccines immunotherapy, researchers believe that these medicines may lead the immune system to act aggressively against COVID-19. According to a retrospective study from New York city cancer patients receiving immunotherapy were at increased risk for severe outcomes from COVID-19 [13]. But on the other hand study find that cancer immunotherapy does not increase risk for melanoma patients [14]. Now researchers discovered that cancer immunotherapy tolls can be use for COVID-19 treatment. They identified the right protein sequence target which used for cancer therapy also use for COVID-19 prevention [15]. Many research and clinical trial is going on optimizing designed vaccine which can maximizing the immune response and disease exacerbation. The main target is to produce vaccine that are safe and effective. Some of the important Cancer immune therapy drug that is under Clinical trials worldwide, are mentioned in Table 2. Now a day's Chimeric antigen receptor (CAR) T-cell therapy is very promising immune therapy which use in cancer treatment [16]. Cytokine release syndrome (CRS) is an overwhelming and potentially life-threatening inflammatory response often seen in cancer patients. The CRS like symptoms  It is an off-the-shelf cryopreserved NK cell product derived from an iPSC that was transduced with a high affinity, ADAM17 non-cleavable CD16 (Fc receptor) that maintains CD16 on the cell surface, which remains fully functional after NK cell activation.
As monotherapy in acute myeloid leukemia (AML) and in combination with CD20 directed monoclonal antibodies in B-cell lymphoma.
Phase I NCT04363346 University of Minnesota Minneapolis, Minnesota, United States

Pamrevlumab
Pamrevlumab is a first-in-class antibody that inhibits the activity of connective tissue growth factor (CTGF), a common factor in chronic fibrotic and proliferative disorders, characterized by persistent and excessive fibrous tissue which can lead to organ dysfunction and failure, and in cancer, characterized by promotion of tumor growth.
In Hydroxychloroquine Hydroxychloroquine is an Autophagy inhibitor, when given in combination with cytotoxic agents have been found to suppress tumour growth and trigger cell death to a greater extent than chemotherapy alone, both in vitro and in vivo.   [18][19]. As a very well-known antiviral drug, Lopinavir-Ritonavir was widely used for laboratory research to treat SARS-Cov-2 prevention. According to a study based on 199 patients, this drug dose not contain any significant effect to clinical improvement and reduce mortality in COVID-19 patients. On 4 th July, 2020 WHO circulated a recommendation to discontinue the use of Lopinavir-Ritonavir after analysis the Solidarity trial interim results [20]. Considering all of this we need to wait until the completion of clinical trial to get new class of emerging therapy is aimed to prevent COVID-19.

Phase II in Previously Treated
In conclusions, COVID-19 pandemic giver very short time to find a proper therapeutic challenge. However, in global emergency, investigations progress rapidly and now phase III trials of new medications already started. As the whole process to approve a new drug which safe and effective, is time consuming. So, several drugs have been re-considered to treat COVID-19 which have been used in cancer therapy. This review considered the cancer immunotherapeutic agents that are potentially suitable drugs consider to treat COVID-19 to accelerate the process. This pandemic generated a endless demand for vaccine all over the world. We should continuing the clinical trial and developing most promising vaccine which can help us not only protect from the current pandemic also help us to gather much knowledge and fill our gaps to protect from future outbreak.

Drug Name
Mode of Action Used for Cancer Therapy Progress in COVID trial

Reference Country
Tranexamic TXA is a synthetic analog of lysine amino acid which reversibly binds four to five lysine receptor sites on plasminogen.