Cancer Immunotherapy: Ups, Downs, & Deaths
There has been a lot of buzz in the cancer research community, oncologists, and the news media about Cancer Immunotherapy. Cancer Immunotherapy is any approach that utilizes some aspect of the immune system to target and kill cancer cells. One therapy, in particular, Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy has been hitting the headlines in more than just positive ways. Reported in Science, Juno Therapeutics has been receiving the negative headlines due to deaths associated with their CAR-T treatments. There have been 7 patient deaths that have all been due to brain swelling (cerebral edema). The trial has been on hold since November and put researchers in the hot seat as they scramble to figure out the underlying cause of the edema. Not so good news for this T-cell based therapy, but others have been historically positive. So what’s going on?
Let’s begin by explaining the development of CAR-T therapy in the simplest of terms. The basic premise behind these therapies is taking the patients’ own T-cells from the body, reprogramming (via genetic engineering) them to attack the cancer cells in the patient, and returning them to the patient to target and destroy the cancer cells.
The process is called Adoptive Cell Transfer (ACT). Whereby, you take the T-cells from the body, expose them to cancer cells of the patient, and allow the T-cells to identify them, causing clonal expansion (expansion of the responsive T-cells). This is great in theory, but in practice, much more difficult to execute. One main hold up is in the fact that the tumor cells that the T-cell need to identify are “Self”, meaning although they are transformed cells, they still originated from you. These T-cells could 1) react to the other tissues of the body and cause an Auto-immune response 2) not recognize specific antigens present on the tumor cells 3) do both (which is still a negative due to the autoimmune response that could trigger death).
Chimeric Antigen Receptor (CAR) Structure
CAR-T cell therapy is based on genetically modifying the T cells of the patient to express a transmembrane receptor called the Chimeric Antigen T-Cell receptor. This receptor consists of 4 domains or parts:
1) Targeting element composed of a Single-chain Variant Fragment (scFv)
2) Spacer & Transmembrane Domain
3) Costimulatory Domain
4) Essential Signaling Domain.
This is a modified protein that recognizes the tumor antigen of choice of the patients’ tumors. It is not a true antibody in a sense but is composed of variable regions of light and heavy chains of immunoglobulins. To put it simply, they mimic antibody structures to give them the specificity they need to target specific antigens (targets).
These targeting domains are made by using genetic sequences that will yield a scFv that will be produced by the T-cells. When the correct scFv is produced, the T-cells making them will be induced to clonally expand. Clonal expansion is the term used to describe the process by which T and B-cells replicate and clone themselves in order to fight infections. In this case, the engineers use this process to produce billions of T cells that precisely target the patient’s tumor cells. The most successful and popular target so far has been CD19, but many other target antigens are currently in clinical trials listed below.
|IL13R alpha 2||CD133||GPC3||HER/EBV||CEA|
Spacer & Transmembrane Domain
The Spacer & Transmembrane Domains are the necessary amino acid sequence to connect the outer portion (target domain) and the inner portion (Costimulatory and Essential stimulatory domains) of the Chimeric Antigen T-cell Receptor. This section of the receptor may not be the sexy part, but it allows the external domains to communicate signals with the interior domains of the receptor. This allows the stimulatory domains to then tell the T-cell to kill the tumor cells.
Costimulatory & Essential Stimulatory Domains
Costimulatory and Essential stimulatory domains are made up of intracellular signaling domains. These include but are not limited to CD28, CD3ζ, and 4-1BB. These are the portion of the CAR that relays signals inside the T-cells to proliferate and to exact their deadliness on the target tumor cells. They are now in the third generation of development where they are adding new domains to maximize their effectiveness. For all intents and purposes, this part of the CAR is the business end of the molecule. The exact effectiveness is still being studied currently, and new intracellular domains are being looked at for efficacy in solid tumor cell targeting.
Targeting of Tumor Associated Antigens helped eliminate some concerns of recognizing “Self”, however, other mechanisms of T-cell suppression can halt the effectiveness of T-cell mediated therapies. The repressive nature of other cellular receptors such as PD-L-1 can cause T-cells to go through a process called anergy, where they functionally shut down and could undergo apoptosis. In clinical development, there are co-treatments of antibodies that would repress this by blocking these other cellular receptors from blocking the CAR T-cells from performing their job. These antibodies are in a class called PD-L1 inhibitors, a very successful one thus far has been Keytruda (Pembrolizumab).
Hurdles To Overcome For CAR T-cell Therapy
Other mechanisms impeding T-cell therapies include suppressive T-cells such as T Regulatory Cells (Tregs). Tregs work by secreting cytokines, or messenger proteins, that shut down the effector/cytotoxic T-cells and prevents them from killing their targets. To eliminate some of these issues, researchers and clinicians have taken steps to maximize immunotherapy treatments. First, to eliminate the suppressive power of Tregs and other T-cells, clinicians will have the patient go through chemotherapy/radiation to deplete the immune system. This depletion step is crucial to the ACT that is used in CAR T-cell therapies. This allows the modified T-cells to repopulate the body after infusion. Tregs serve a normal function in the body by balancing out the immune system, dysregulation in Tregs has been indicated in some autoimmune diseases. Unfortunately, cancer cells utilize Treg function in a pro-tumorigenic way.
These hurdles alone have not deterred researchers from coming up with novel solutions to the vaunted immunotherapies. Now, the task at hand is to alleviate the systemic symptoms of using immunotherapies. The edema of the brain has been known for some time, but not to the extent seen in recent trials. There is still the risk of graft-versus-host disease where the CAR T-cell recognizes self and causes an autoimmune response. Another very dangerous outcome is Cytokine Release Syndrome (CRS), where there is a quick and large dissemination of cytokines (messenger molecules used by the immune system to find antigens, bacteria, etc.) into the bloodstream that causes the immune system to go into hyper drive.
This could be followed by organ failure and death. Some milder symptoms are fever, inflammation, low blood pressure, and other symptoms associated with an immune response (some of the very same symptoms you experience when you catch a cold or get the flu). These lesser symptoms can usually be managed with existing drugs such as steroids and etanercept (Enbrel).
One big key hindrance for this therapy that I have failed to mention is that it is not for all types of cancers. Specifically, large solid tumors are very difficult to treat via this method. The key factor to this is that the CAR T-cells cannot penetrate the tumor deeply enough to target all the tumor cells. The fact that the solid tumors are just that, solid, keeps the CAR T-cells from being able to infiltrate it deeply. Plus, remember those Tregs? Those cells can still be present inside of solid tumors even after the depletion therapy that is performed on the patient. These Tregs will suppress the CAR T-cells and hinder their ability to destroy the tumor. These are just some of the issues of using CAR T-cell therapy in attacking solid tumors
What’s Next For CAR T-Cell Therapy?
Despite the drawbacks and setbacks mentioned above, the future of immunotherapies remains bright, as 2 companies other than Juno Therapeutics (Kite Pharma and Novartis) did not have any deaths in their trials and will be applying for new drug status within the year (barring any unexpected adverse events). Regardless, the deaths are tragic and sad, but they make scientists reassess and come up with better treatments and therapies to give others a fighting chance. The progression of immunotherapies from the current targets of melanoma and blood cancers to the solid tumor varieties will take ingenuity and out of the box thinking. Currently, most of the therapies described here only target non-solid tumors, but next-generation treatments will begin to target tumors of the solid type including colorectal cancer, non-small cell lung cancer, prostate cancer, breast cancer, etc. This will be the true test of this technology and the researchers behind them.