Cancer: A Genetic and Immunological Disorder

by Praveen Bommareddy

Goal: The primary goal of my blog series is to contribute to SITC’s mission in educating patients, clinicians, and researchers about the recent advancements in immunotherapy. I am particularly interested in the use of genetically modified (non-pathogenic) viruses as immune modulators for cancer treatment. 

In this introductory edition of my blog series, I would like to provide an overview of cancer immunotherapy and a brief description on why immunotherapies may not always work well due to heterogeneity in tumor phenotypes and various mechanisms that suppress immune response against cancers.

Target audience: Patients and their families, clinicians, and researchers.

The advancement of basic and translational research has enabled modern medicine to prevent, cure, and subdue many human diseases. While many diseases are controlled by current treatment strategies, cancer still remains a major threat to mankind. Globally, 1 in 6 deaths are due to cancer (WHO). In 2018, an estimated 1,735,350 new cases of cancer will be diagnosed in the United States (American Cancer Society). 

In brief, cancer occurs due to over-activation of cell proliferation pathways such as RAS, RAF, MAPK, or by deletion of tumor suppressor genes such as P53, RB1, BRCA1, and BRCA2 that normally control unwanted cell proliferation (American Society of Cinical Oncology). Traditional cancer therapies are developed mostly to target replicating DNA, but scientists soon realized that these drugs would also kill normal replicating cells. 

Ancient physicians and surgeons began treating cancer by surgical removal of tumors, but they realized that tumors grow back in most cases. Although medicine advanced over the course of history, not much progress has been made in cancer treatment until the 21ᔆᵀ century. Recurrence of disease is the most common problem associated with targeted therapies.

Many cancers are associated with mutations (deletions or substitutions) in genes which control cell proliferation. These mutations in genes can lead to the formation of abnormal proteins (neo-antigens), which should be detected and cleared by the body’s immune system. 

Most recently, scientists have discovered that cancers hide from the immune system by releasing immune suppressive factors and by creating cellular and physical barriers that can limit the ability of immune system to attack tumors. Thus, recent insights in cancer biology have led researchers to understand that cancer is not only a genetic disease, but also an immunological disease. 

Treating cancer using immunotherapies began enthusiastically during the late 20ᵀᴴ century, but it did not gain prominence until 1990, when Dr. James Allison and colleagues discovered immune checkpoint inhibitors. Immune checkpoint inhibitors rejuvenate the exhausted tumor-fighting cells and restore anti-tumor immunity. During the last five years, cancer immunotherapy has begun to set new standards for cancer therapy; today many immunotherapies, such as immune checkpoint inhibitors, programmed cell death protein-1 (PD-1; keytruda), Cytotoxic T-lymphocyte associated antigen-4 (CTLA-4; Opdivo), oncolytic viruses (Imlygic), cytokine therapies such as Interleukin-2 (IL2), and cell therapies such as chimeric receptor antigen T cells (CAR T) are used as standard therapies for select patients across various cancer types.

Currently, immune checkpoint inhibitors are the most popular first line immunotherapies for several cancer types, but they often fail to work in tumors that are poorly infiltrated with immune cells. Immune-modulatory cytokines such as IL2 and Granulocyte Macrophage Colony Stimulating Factor (GMCSF) can stimulate and activate immune cells, but their use is not favorable due to associated toxicities and limited bioavailability to tumors via systemic administration. Cell therapies such as adoptive cell transfer (ACT), including CAR T cell therapies, can be used to deliver immune cells against desired tumor antigens. 

Finally, vaccines using dendritic cell (DCs) loaded with desired tumor antigens are also being used to enhance tumor specific immune responses. Vascular barriers and other immune escape mechanisms developed by tumors might limit the use of cellular and vaccine therapies. 

Another unique class of immunotherapy agents include native or genetically modified viruses, termed as oncolytic viruses (OVs). Genes associated with pathogenicity are often deleted in OVs to enhance safety. (I will describe the use of OVs, the advantages, and limitations in more detail in my next blog). OVs can act as immune modulatory agents by activating innate and adaptive immune responses. Many of the above-mentioned immunotherapy agents might not always be effective due to complexity in tumor phenotype across cancer types. Many cancers exhibit a complex phenotype that can foster tumor progression and suppress anti-tumor immunity. Tumor phenotype plays a crucial role in determining the response to many immunotherapy agents. 

Recently, Drs. Ira Mellman and Dan Chen described the three common immunological phenotypes exhibited by tumors: the inflamed tumors, immune desert tumors and immune excluded tumors, collectively known as “cold tumors”. Inflamed tumors are often referred to as “hot” tumors, as they are generally composed of immune cells such as CD8+ T cells, regulatory T cells, and myeloid suppressor cells; often these cells exhibit exhaustion phenotypes. Checkpoint blockers and other immunotherapies are shown to work well in the hot tumor phenotype. 

The other two phenotypes are often referred as "cold": the immune desert phenotype is characterized by immunological ignorance and immune tolerance due to the absence of neo-antigens, danger signals, and loss of MHC1, which is required for presentation of tumor derived antigens by DCs to T cells (this process is termed as cross presentation). Lastly, the immune excluded tumors are composed of vascular factors, barriers, and stromal based inhibition leading to the inhibition of immune cell infiltration. Selecting the right immunotherapy for the right tumor type is the key to precision immunotherapy.

In my future blogs, I will discuss in detail the mechanisms of action of oncolytic viruses and the potential strategies for the use of OVs in converting between tumor phenotypes, for example converting the “cold” tumor to a “hot” tumor.

Disclaimer: This blog is strictly based on my opinion and my understanding of current literature.