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.  (T-cells are a kind of blood cell biologists refer to as the “soldiers of the immune system”.)  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.

It is worth noting that biologists distinguish between the innate immune system, which is not fine tuned to specific foreign materials, and the adaptive system.  The adaptive system is more complex because it responds to the environment and creates antigens only after the body is exposed.

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 conventional 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.  Blockade of immune checkpoints is therefore 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. In the body, 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 including melanoma, non-small cell lung cancer, renal clear cell carcinoma, Hodgkin’s lymphoma and urothelial carcinoma. Monoclonal antibodies drugs include Nivolumab (Opdivo®), pembrolizumab (Keytruda®) and Atezolizumab (Tecentriq®) and are delivered by intravenous injection or infusion.

Treatment Vaccines

A vaccine for cancer may seem too good to be true, but the use of vaccines to treat cancer is being investigated.  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.

A vaccine fights infection by enabling the body’s natural immune system to better recognize the pathogen. Immune cells called T cells and B cells look for specific antigens, usually small pieces of cells or viruses that the immune system recognizes as foreign, and then reproduce themselves to better fight the antigens they have found. T cells identify and kill cells or viruses that contain the antigen, and B cells produce antibodies that attach to the antigen and kill the cell or virus by indirect means. Each T and B cell recognizes a different antigen, and when it finds its target, it makes many copies of itself. This way, the body targets the invasion by reproducing the cells that go after the specific substance that has already been identified as foreign. A vaccine just gives the immune system a head start in this very same process. A vaccine for smallpox contains smallpox viruses that are somehow disabled so that they cannot infect the vaccine recipient. When the viral particles enter the cell, the T cells and B cells that recognize the virus replicate themselves, so the immune system already has plenty of cells looking for smallpox viruses when the real viruses actually arrive. The viruses are then attacked immediately upon entrance into the body and never get the chance to start an infection. The vaccine triggers the natural immune response so that it is underway before the pathogen even enters the body. Vaccines have a big potential advantage over chemotherapy; while chemotherapy can kill tumor cells immediately, their effect on cancer as a disease may last only weeks or months. Vaccine-induced tumor regression, by contrast is more long-lasting.

Vaccines are intended to activate the patients’ immune cells, and trigger a response against the cancer cells. 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 (lymphocytes) 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.

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.

Early use of vaccines.

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.  T cell actions are specific, and can potentially distinguish between healthy and malignant cells, making T cell therapy among the most precise of targeted therapies.  T cell responses have memory, and the therapeutic effect could go on for years after initial treatment.

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.

ACT

Adoptive cell 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.  See our page on adoptive cell transfer therapy.

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.

It was reported in 2017 that over 1000 immunotherapy clinical trials were underway.

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

 

Axicabtagene ciloleucel

Brand/Trade Names: Yescarta

Formula: N/A

Mechanism: adoptive cell transfer therapy

Class: Chimeric antigen receptor (CAR)

Administration: Intravenous

Notes: Granulocyte – colony stimulating factor. This is a truly personalized therapy and is made from the patient’s own immune system cells in a process called adoptive cell therapy. http://chemoth.com/immunotherapy#act

Only a few hospitals in the US can give this treatment. The drug company lists them here: https://www.yescarta.com/treatment-centers

Fludarabine Phosphate

Brand/Trade Names: Fludara

Formula: N/A

Mechanism: adoptive cell transfer therapy

Class: antimetabolite

Administration: Intravenous

Notes: Granulocyte – colony stimulating factor. This is a truly personalized therapy and is made from the patient’s own immune system cells in a process called adoptive cell therapy.

Tisagenlecleucel

Brand/Trade Names: Kymriah

Formula: N/A

Mechanism:

Class: immunotherapy

Administration: Intravenous

Notes: CAR T-Cell

Filgrastim

Brand/Trade Names: Neupogen, Granix, and Zarxio

Formula: C845H1343N223O243S9

Mechanism: hematopoietic agent

Class: biologic response modifier

Administration: Intravenous

Notes: colony stimulating factor

Talimogene Laherparepvec

Brand/Trade Names: Imlygic, T-VEC

Formula: N/A

Mechanism:

Class: immunotherapy

Administration: Intravenous

Notes: genetically engineered herpes virus