Immunotherapy for Cancer Treatment

The immune system is probably second only to the nervous system in complexity.  Immunotherapy is a technology whereby the immune system is supplemented by external materials or induced to recognize as a disease something it previously let go.  The immune system does stop the development of tumors all the time; we just don’t recognize it.  (That’s why people with weakened immune systems get cancer more often that those with good immune systems.)  However, sometime cancer can hide from the T-cells.  Immunotherapy either makes the malignant cells more recognizable to immune system detection or increases the killing power of the immune system.  Goals are:

  • Stopping or slowing the growth of tumors
  • Stopping cancer from metastasizing to other parts of the body
  • Helping the immune system work better at destroying cancer cells

How do cancer cells evade the immune system?

Crafty cancer cells figure out a way to reduce the chemical markers – antigens – on their surfaces, thereby making it difficult for immune system components to identify the malignant cells as unusual and worth attacking.

They can also wage chemical warfare with the immune system, and produce chemicals that disable the T-cells.

Is it really chemotherapy?

Also called biologic therapy, immunotherapy is often classified as a different type of cancer treatment from chemotherapy.  The active agents are different from old-style chemo, but the process involves giving chemicals (sometimes very large and complex molecules) to patients in formats like intravenous injection, so we include immunotherapy as a type of chemotherapy.

Administration

Like chemotherapy, immunotherapy is given through intravenous tubes (direct to the bloodstream). Sometimes the medicine is given directly to bladder through a catheter (intravesical administration), or a pill or topical solution if the active molecules can enter the body that way.

Patients get immunotherapy at the same places that get traditional chemotherapy; a hospital or clinic is a common location and it is often an outpatient situation.

Types

Immunotherapies either stimulate the activities of specific components of the immune system or counteract signals produced by cancer cells that suppress immune responses.

Immunomodulatory antibodies

Cytokine therapy is the most widely used type. The body makes interferons and interleukins, and these can be employed in immunotherapy. Externally produced agents (synthetic cytokines) are injected to supplement the patient’s immune system.  These are sometimes called non-specific immunotherapies as they are employed for more than one disease (or one type of cancer).  The adaptability of the immune system allows it to combat many threats, and sometimes these supplements can help the system defeat the cancer.

Monoclonal antibodies, on the other hand, are very specific.  They are a form of targeted therapy.  By attaching to a specific protein on a malignant cell, they make that cell a bigger target for the immune system’s killer cells to eliminate.  Monoclonal antibodies can supplement the immune system by directly attacking malignant cells or other targets in the body.  Some antibodies that oncologists employ only mark the malignant cells (this is sometimes called targeted therapy), so the natural immune system components can attack it.  

Checkpoint inhibitors

Checkpoint inhibitors are usually monoclonal antibodies also – these fiddle with the internal feedback mechanism of the immune system.  Immune checkpoints represent inhibitory pathways regulating the immune system. They play critical roles in maintaining self-tolerance and modulating the duration and amplitude of the immune responses. In tumors, inhibitor checkpoints often confer tolerance to, and evasion from the immune response. Thus, blockade of immune checkpoints is a promising approach to activate therapeutic antitumor immunity.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4)

CTLA-4 is one of the major negative regulators of the immune response. Blocking CTLA-4 with Monoclonal antibodies turns off the inhibitory mechanism and allows the immune cells to destroy the tumor. The drug Ipilimumab, delivered by intravenous injection (trade name Yervoy®), is FDA-approved for the treatment of Melanoma.

Programmed death 1 (PD1)

PD1 is an inhibitory receptor expressed on the surface of activated T-cells, B-cells and natural killer cells. Under physiological conditions, PD1 binding to one of his ligand limits the activity of T-cells in peripheral tissues during inflammatory processes, preventing autoimmune disorders, PD1 ligands are frequently upregulated on cancer cells, preventing the anti-tumor immune activity.

Monoclonal antibodies inhibiting PD1 activity were approved by FDA for a number of tumors, mainly Melanoma, non-small cell lung cancer, renal clear cell carcinoma, Hodgkin lymphoma and Urothelial carcinoma. Monoclonal antibodies drugs include Nivolumab (Registered name Opdivo®), pembrolizumab (Registered name Keytruda®) and Atezolizumab (Registered name Tecentriq®) and are delivered by Intravenous injection or infusion.

Treatment Vaccines

We usually think of vaccines as part of preventative medicine, but there are vaccines created to treat cancer.  Researchers are looking into immune cell vaccines, peptide vaccines, and tumor cell vaccines.  Even more cutting edge are viral vector vaccines and nucleic acid vaccines. While still largely in the realm of experimentation, some have been approved by the FDA.

Vaccines are intended to activate the patients’ immune cells, and trigger a response against the cancer cells. However, suppression of the immune system by the growing tumor affects the vaccine ability to induce a strong immune response at the tumor site. Currently, vaccines for the prevention of cancer are being developed  The first prophylactic cancer vaccines act indirectly by preventing infection with viruses known to cause cancer. Two of these vaccines, Gardasil® and Cervarix®, target and prevent human papilloma virus infection, responsible for over 70% of cervical cancers.

The FDA-approved therapy Provenge also involves external modification of patient cells.  Blood is extracted, and white blood cells are isolated.  The lymphocytes are modified to attach to prostate cancer cells.  The immune system acquires the ability to recognize and destroy antigens associated with prostate cancer.  Bacillus Calmette-Guérin (BCG) is used for treatment of bladder cancer.  These are therapeutic vaccine systems, not fully general but not personalized either.

Vaccines are intended to activate the patients’ immune cells, and trigger a response against the cancer cells. However, suppression of the immune system by the growing tumor affects the vaccine ability to induce a strong immune response at the tumor site. Currently, vaccines for the prevention of cancer are being developed. The first prophylactic cancer vaccines act indirectly by preventing infection with viruses known to cause cancer. Two of these vaccines, Gardasil® and Cervarix®, target and prevent human papilloma virus infection, responsible for over 70% of cervical cancers.

At the extreme a vaccine is crafted for the specific patient.  This is a form of personalized therapy (it’s hard to imagine anything more personalized.)  A biopsy of the cancer tissue is used to create the vaccine in a lab and then is inserted into the patient’s bloodstream.  Ideally the vaccine attacks both the cells in the primary tumor and cancer cells around the body, preventing micrometastasis.

T-cell therapy

T-cells are part of the immune system, and one form of t-cell therapy is simply removing the cells from the patient, cultivating them in the lab (i.e. producing a lot more cells), and reinjecting them into the body.  A more nuanced method is like that for the vaccine Provenge.  In chimeric antigen receptor (CAR) T-cell therapy, the cells are modified to increase the receptors for cancer cells.

Recognition of peptides by T-cells is not sufficient to trigger an effective immune response, and additional signals are needed to stimulate proliferation, activation and differentiation of T-cells.

Monoclonal antibodies (MAb) binding to co-stimulator receptors on T-cells have been developed. Urelumab MAb targeting a T-cell antigen has demonstrated clinical activity in melanoma. However, its further development and use were hindered by its toxicity.

Oncolytic virus therapy

Oncolytic virus therapy is not the same as cancer vaccines.  In OVT a selected virus is injected into the tumor.  It enters tumor cells where it multiplies and frequently kills the cells.  Antigens are released from the dead cancer cells; these antigens are specific to the malignant cells.  The body’s immune system then attacks other (cancerous) cells that have the same antigens.  This is a way of increasing the action of the immunotherapy.

The FDA approved talimogene laherparepvec (Imlygic), or T-VEC for treatment of melanoma.  This virus is a modified form of the herpes simplex virus.  Research continues on oncolytic virus therapy for other types of cancer.

Adoptive cell transfer

This is an exciting new technology that may be classified as immunotherapy.  It involves removal of white blood cells called T-cells from the tumor.  The logic is that these particular T-cells have identified the tumor as something they want to fight.  There might be some genetic modification of the cells and then the cells are cultured (grown in the lab).  The cells are then reinserted to the patient with the hope that they will fight the cancer.

Adoptive call therapies are based on ex-vivo manipulation of immune cells to enhance their anti-tumor activity. The cells are isolated from either the peripheral blood or the tumor, undergo expansion or other manipulation and are reinfused into the patient. Here, we will focus on Chimeric antigen receptor (CAR) T-cell therapy.

CAR T-cell Therapy

CARs are engineered antigen receptor proteins consisting of an antigen binding region and T-cell receptor signaling domains. When injected into a patient they both recognize the tumor and attack it.

CD 19 is an antigen domain present on nearly every cancer cell of a patient. It is specific to cancer cells and non-essential tissues, and therefore constitutes an ideal target for treatment. Clinical studies with CAR T-cell therapy targeting CD19 T-cell antigen have been successful in the treatment of B-cell acute lymphoblastic leukemia.

A future goal will be to select new tumor antigens for a broader range of cancers.

Dangers

The immune system is complex.  It’s full of negative feedback loops, cross-checking systems.  That’s partly why immunotherapy is dangerous in clinical practice.  If you start putting in new antibodies, stimulating the system to amp up response to given objects, or blunt the response, you run the risk of doing more harm than good.

One big problem with personalized therapy is that even when scientists can identify specific targets for immunotherapy for a given patient, it takes a year to work out a solution.  Cost considerations aside, a cancer patient may not have a year of life expectancy.

Researcher Robert Schreiber and his group have developed an idea called cancer immunoediting. The idea is that some of the mutations in the cancer cells can be detected by the immune system and that by attacking and destroying those cells, the immune system effectively edits the tumor. The remaining malignant cells might go dormant or they may grow in an immune system – resistant tumor.

One area scientists are looking into involves trace biomarkers that may be detected at a cellular level.  Mutations present in some cancer cells could result in production of proteins that only the malignant cells make.  If scientists can identify those proteins and create vaccines that identify the proteins in the body, those vaccines may spur the immuno-system into action to attacking the malignant cells.

Overview article: Immune System Modulation:  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4264429/

Many additional immunomodulating agents currently are under development, opening new directions for cancer treatment.

See Lohmueller J, Finn OJ. Current modalities in cancer immunotherapy: Immunomodulatory antibodies, CARs and vaccines. Pharmacology & Therapeutics.2017;178:31-47.