Immuno-oncology (IO) is the buzz word today and it has everyone doing IO research. Why are IO therapies buzzing today? If we look back at the history of cancer treatment, the survival rate was measured in months, which according to oncologists was a lot back then, because the mortality rate in most cancers was 100%. Most traditional chemotherapies were not well tolerated, because they would kill both cancerous and healthy cells, leading to major side effects such as loss of hair, nausea and vomiting, and risk of infection. Survival was sometimes better, but not much better, depending on the type of cancer and the patient's own genetic and physiological make-up. The big advantage of IO therapies is that they can target specific receptors on the cancer cells and destroy them while leaving the healthy cells alone. This will also help reduce some of the traditional side effects when healthy cells are destroyed.
Scientists have tried to solve the targeting problem by utilizing the patient’s own immune system to aid in recognizing and killing the cancer cells, rather than healthy cells, in that way keeping the cancer cells at bay. Scientists have tried and are still developing drugs that fall into two categories of IO:
1) Checkpoint Therapies - which include cytokine therapy, therapeutic vaccine (dendritic cell vaccines), antibody drug conjugates and tumor specific T cell; and
2) Adoptive Cell Transfer (ACT) therapies - tumor infiltrating lymphocytes (TILs) from tumor mass that is excised, and gene transfer methods: Chimeric Antigen Receptors (CAR) T cells and TCR (T-cell receptor) T cells for blood.
Checkpoint Therapies
Checkpoint therapies currently on the market are Merck & Co.’s pembrolizumab (Keytruda®), Bristol Myers Squibb (BMS)/Ono's nivolumab (Opdivo®), and Genentech's atezolizumab (TECENTRIQ™) for specific types of cancers and have made significant inroads with some patients being cancer free. Both Keytruda and Opdivo are human monoclonal antibodies that block the interaction between PD-1 and its ligands, PD-L1 and PD-L2, that inhibits the body's immune response, including anti-tumor immune response. Atezolizumab is a monoclonal antibody that binds to PD-L1 and blocks its interactions with both PD-1 and B7.1 receptors.
BMS' second monoclonal antibody ipilimumab (Yervoy®), binds to CTLA-4 and blocks the interaction of CTLA-4 with its ligands, CD80/CD86, that also inhibits T-cell activation and proliferation.
PD-1, as the name suggests, is a checkpoint protein on T-cells. It acts to "turn off the T-cells and prevent them from attacking other cells in the body when it attaches to PD-L1, a protein on some normal (and cancer) cells. When PD-1 binds to PD-L1, it tells the T-cells to leave the other cells alone, which unfortunately also applies to cancer cells that have large amounts of PD-L1 and this is how they evade immune attack.1 CTLA-4 works in the same manner as PD-1/PD-L1.
Monoclonal antibodies that target either PD-1, PD-L1, or CTLA-4 can boost the immune response by not turning off the immune system as they kill the cancer cells. This therapy has shown a great deal of promise in treating certain cancers.
Other monoclonal antibodies in the pipeline include MPDL-3280A, by Roche/Genentech/Chugai; MED-14736, by AstraZeneca/MedImmune; and most recently Tioma Therapeutics, Forty-Seven and Trillium Therapeutics, all with checkpoint inhibitors that target CD-47.2 All these companies are looking to expand their indications for various types of cancers with their respective monoclonal antibodies.
The tumor responses observed with both CTLA-4 and PD-1/ PD-L1 pathway inhibition has reached the 10- year mark for some melanoma patients treated with ipilimumab who have not required any treatment for many years.3
Adoptive Cell Transfer (ACT) Therapies
CAR-T therapies specifically have had some impressive results. It involves reprogramming the patient's own T-cells to recognize cancer cells and bypass healthy or normal cells.
What are CAR-T cells? A CAR gene has two major components; 1) an external receptor that recognizes an antigen binding site on the cancer cells and 2) an internal component or signaling/expression that directs the T-cell to the cancer binding site and is inserted into a T-cell via a retrovirus or lentivirus vector. See Image 1.
How do they work?
Scientists have been working on CAR-T cells for over a decade and they developed the first generation of CAR-T back in 1991, for HIV. This first generation CD4/CD8z (CD4/CD8 Tcells) + CD3 - (zeta) chain (to generate an activation signal in T lymphocytes), CAR-T for HIV (CD4) using a retrovirus went into clinical trials in 1997, the CAR-T cells persist now for 10 years.4
The second and third generation of CAR-T uses a single chain fragment variable (scFv), or antibody fragment, as the external component designed with the internal signaling CD28 and/or 4-1BB (CD137) + CD3 -chain. Immunologists have found that they needed two (2) signals: Signal 1 for activation and Signal 2 for survival for T-cell proliferation. 5,6,7 Scientists discovered that if you have signal 2 but not signal 1, it has no effect on T-cell. If you have signal
1 but no signal 2, there is inactivation (anergy), or deletion of T-cell.8 Scientists also believe that the microenvironment plays an important role in the immune system.
To make these cancer-fighting T-cells or CAR-T cells, T-cells are first collected from the patient and then modified to recognize an antigen binding site on the cancer cells. It usually takes 2 1/2 to 3 weeks to insert the gene and grow cells. Once this is accomplished, the modified T-cells are then infused back into the patient, or autologous therapy.
Once infused back into the patient these "programmed" T-cells can multiply and persist for a long time ("living drug"), they are capable of destroying any cells that have the target antigen.
This disruptive technology of modifying T-cells is similar to monoclonal antibody therapy, as it does use a fragment of an antibody, but has more potency and persistence - as living cells that can persist in the body, as opposed to antibodies (proteins) that are active for a limited time.
What is the efficacy in cancer treatment?
Three (3) different CAR-T therapies for leukemia from Memorial Sloan Kettering Cancer Center (MSKCC), the National Cancer Institute (NCI) and University of Pennsylvania, (UPenn) were compared. There was a 90%, 80% and 90% complete response (no cancer present) for Acute Lymphocytic Leukemia (ALL) respectively in a small number of patients. This is the type of efficacy data that's got everyone very excited about CAR-T therapy, (UPenn),9 (MSKCC),10 (NCI)11. The results for Chronic Lymphocytic Leukemia (CLL) were not as successful, primarily because it's a more complex disease to tackle. Nevertheless, many companies are focusing on this area.
Emily Whitehead, the first pediatric patient with ALL treated with CAR-T therapy at the Children's Hospital of Philadelphia (CHOP), was a complete responder in 2012. She remains cancer free after 4 years and counting. When President Obama announced the Precision Medicine Initiative in January 2015, Emily was invited to the White House to personalize a successful example of Precision Medicine or Personalized Medicine.
It's too early to tell for sure, but one of the advantages of CAR-T therapy appear to be that it's a "living drug;" scientists are able to reprogram the patient's T-cells into CAR-T cells which are permanently adapted by the body to kill cancer cells. It's anticipated that this therapy may become a one dose "cure."
There are a number of companies researching this hypothesis: Bellicum Pharmaceuticals, Celegene/bluebirdbio, Cellectis/Pfizer, Juno, Kite/Amgn, Novartis, Ziopharm to name a few.
There are and will be many more companies working in this field for various types of cancer.
While CAR-T therapy sounds promising, like any other drug, there are side effects associated with its use, Cytotoxicity Release Syndrome (CRS) being one of them. The reaction’s been managed successfully with an IL-6 inhibitor. Therefore, scientists are still trying to perfect the design of the CAR gene, to eliminate or reduce the incident of side effects while trying to develop a CAR-T cell that will be efficacious in all types of cancers.
Conclusion
The worldwide market for cancer immunotherapies is anticipated to grow from $1.1B in 2012 to $9B in 2022, a 23.8% annual growth rate.12 Leading the growth for now are the immune checkpoint inhibitors, but the CAR-T therapies may outpace them. Scientists are also looking at combination therapies with checkpoint inhibitors and CAR-T therapy, that would attack cancer cells from all angles and promote better efficacy and fewer side effects.
The advanced technology that scientists have developed today is extraordinary. We may one day have a "cure" rather than a "remission" in cancer therapy. This would've been considered fiction 25 years ago. With the rising cost of healthcare, IO therapy will certainly curb healthcare costs and people will live longer.
1. http://www.cancer.org/treatment/treatmentsandsideeffects/treatmenttypes/immunotherapy/cancer-immunotherapy-immunecheckpoint-inhibitors
2 http://www.xconomy.com/san-francisco/2016/08/16/with-new-name-and-86m-tioma-to-explore-anti-cd47-cancertherapy/?utm_source=Xconomy&utm_campaign=a5b414c3c9-NEWSLETTER_all_stories&utm_medium=email&utm_term=0_2aa91c0bc9-a5b414c3c9-288454541
3 http://www.onclive.com/publications/contemporary-oncology/2014/February-2014/Immune-Checkpoint-Blockade-in-Cancer-
Inhibiting-CTLA-4-and-PD-1PD-L1-With-Monoclonal-Antibodies?p=4#sthash.pffgzSGU.dpuf
4 June, Carl. 2015, "Cells: from Robert Hooke to Cell Therapy – a 350 year journey," the Royal Society scientific programme,