Sunday, December 4, 2016

Carpet Bombing Cancer

The immune system is a powerful attack system. Take the simple example of the common cold. You touch something, or someone coughs and sends particle towards you. The virus enters your nose. Then what? The immune system recognizes this new adversary, the virus, and it sends out warning signals, recruits immediate responders, and at the same time the virus multiplies the immediate immune system releases a volume of cytokines, killer proteins to carpet bomb everything in the path of the virus. The nose starts running, the throat gets sore, the lungs get congested as the battle between the growing virus load is slowly overcome by the ever faster growing immune response. So what makes us feel so bad with a common cold? It may very well be the immune system response rather than the attack.

Now consider working in the garden. Peaceful. Relaxing, at least for some. Then as you dig up weeds, you notice you just unearthed roots that attache to that shiny three leaves plant. Poison Ivy! But no immediate response, you go in and wash your hands, and thinks all is well. No luck. Slowly you start itching and have wheals all over your hands and arms. Again the near immediate response. Your immune system is after that interloper.

These two examples show how this protector of our lives can makes us worse off. It carpet bombs any attacker.

The NY Times notes[1]:

Another recent paper found that 30 percent of patients experienced “interesting, rare or unexpected side effects,” with a quarter of the reactions described as severe, life-threatening or requiring hospitalization. Some patients have died, including five in recent months in clinical trials of a new immunotherapy drug being tested by Juno Therapeutics Inc. The upshot, oncologists and immunologists say, is that the medical field must be more vigilant as these drugs soar in popularity. And they say more research is needed into who is likely to have reactions and how to treat them. “We are playing with fire,” said Dr. John Timmerman, an oncologist and immunotherapy researcher at the University of California, Los Angeles, who recently lost a patient to side effects. The woman’s immunotherapy drugs had successfully “melted away” her cancer, he said, but some weeks later, she got cold and flulike symptoms and died in the emergency room from an inflammatory response that Dr. Timmerman described as “a mass riot, an uprising” of her immune system. “We’ve heard about immunotherapy as God’s gift, the chosen elixir, the cure for cancer,” he said. “We haven’t heard much about the collateral damage.”
Unlike chemotherapy, immunotherapy can be long lasting. For example, the CAR-T cells which we have discussed are the patient's cells genetically engineered to recognize cell surface markers and when seen destroy the cancer cell. That would be fine if and only if the cells destroyed are cancer cells. However, there may be unintended consequences. First, there may be other cells which we do not yet fully understand that express the same or similar surface marker. They then also become targets. Second, and this is an issue, is that the process of destruction may have a lot of surrounding cells getting mascaraed, due to the released cytokines. This is collateral damage. Third, the collateral damage must be gotten rid of and this is part of the function of the immune system and this may be some positive feedback loop resulting in a set of catastrophic systemic failures.

Unlike chemotherapy, which is some chemical which kills certain types of cells, say rapidly reproducing ones, thus killing cancers as well as say hair. Immunotherapy may be long lasting if not permanent. You just can't stop administering it. Once started it may last forever, or at least until the patient dies. However, some recent work demonstrates that T cells do get "exhausted".[2]  The authors note:

During cancer or chronic infection, T cells become dysfunctional, eventually acquiring an “exhausted” phenotype. Immunotherapies aim to reverse this state. Using a mouse model of chronic infection, two studies now show that the epigenetic profile of exhausted T cells differs substantially from those of effector and memory T cells, suggesting that exhausted T cells are a distinct lineage (see the Perspective by Turner and Russ). Sen et al. defined specific functional modules of enhancers that are also conserved in exhausted human T cells. Pauken et al. examined the epigenetic profile of exhausted T cells after immunotherapy. Although there was transcriptional rewiring, the cells never acquired a memory T cell phenotype. Thus, epigenetic regulation may limit the success of immunotherapies.

However, there is an explosion of new markers and CAR-T cell targets. Juno Therapeutics lists some of the surface targets which their therapeutics address[3]. They are:

CD19… a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.

WT-1: …high-affinity TCR T cell product candidate targets WT-1, an intracellular protein that is overexpressed in a number of cancers, including adult myeloid leukemia, or AML, and non-small cell lung, breast, pancreatic, ovarian, and colorectal cancers.

CD22…Like CD19, CD22 is a cell surface marker for lymphocytes that is present on most B cell malignancies, including acute lymphoblastic leukemia and various subtypes of non-Hodgkin lymphoma, including diffuse large B-cell lymphoma.  Importantly, CD22 expression has been shown to be maintained in acute lymphoblastic leukemia that has lost CD19, making anti-CD22 CAR T cells a potential combination or follow on therapy for CD19 CAR T cells.

L1-CAM…also known as CD171, is a cell-surface adhesion molecule that plays an important role in the development of a normal nervous system. It is overexpressed in neuroblastoma, and there is increasing evidence of aberrant expression in a variety of solid organ tumors, including glioblastoma and lung, pancreatic, and ovarian cancers. Our L1CAM product candidate was originally developed at SCRI.

MUC-16 / IL-12…a protein overexpressed in the majority of ovarian cancers, but not on the surface of normal ovary cells. CA-125 is a protein found in the blood of ovarian cancer patients that results from the cleavage of MUC-16. CA-125 levels in the blood are a common test for ovarian cancer progression because they correlate with cancer progression. Our MUC-16/IL-12 product candidate, which was originally developed at MSK, has a binding domain that recognizes an extracellular domain of MUC-16 that remains following cleavage of CA-125.  Our MUC-16/IL-12 product candidate is our first development candidate that uses our “armored” CAR technology.

ROR-1…a protein expressed in the formation of embryos, but in normal adult cells its surface expression is predominantly found at low levels on adipocytes, or fat cells, and briefly on precursors to B cells, or pre-B cells, during normal B cell maturation. ROR-1 is overexpressed on a wide variety of cancers including a subset of non-small cell lung cancer, triple negative breast cancer, pancreatic cancer, prostate cancer, and ALL. It is expressed universally on B cell chronic lymphocytic leukemia and mantle cell lymphoma. Our ROR-1 product candidate was originally developed at FHCRC.

One major concern is that of targeting the right cell. We assume that we can identify a specific cell by its unique surface marker. We design a specific immune targeting mechanism that goes after that cell. But if we believe in the stem cell theory of cancer, we more than likely have not targeted the stem cell. We have targeted some of it proliferations but not control elements. In fact, I would be willing to bet we have not targeted the stem cell. Thus, any immunotherapy may just make cancer a chronic illness but would not be curative. One then would be concerned by the continuing mutations.

Immunotherapy is a derived or indirect therapy. It is derived from examining how cancer cells are different, based upon surface markers. It is indirect because it deals with a secondary effect of the failing cell. It does not care what the problem is inside the cell but just that it has a different cell marker. In contrast the pathway methods whereby we know what pathway element is defective addresses a specific direct defect. This is a directed therapy.

Immunotherapy has a wealth of tools. T cells, NK cells, CAR-T cells Mabs, IL variations and the likes. To a degree, they are all a step up from chemotherapy but do not necessarily represent a panacea. There are two things we must do. First identify the stem cell and its characteristics. Second, eliminate the stem cell or fix the genetic fault. Until then we will always have the unintended consequences.