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By Brian Koffman, MDCM
Immunotherapy is most broadly defined as any treatment that uses a person’s own immune system to fight cancer by boosting or changing how the immune system works so it can better find and attack cancer cells.

When it uses living sources, as it often does, to produce the treatment “drug”, immunotherapy is also classified as a type of biological therapy.

I will focus on CLL in this overview, though much of what is explained would be of interest to anyone battling cancer.

First, let me deal with two classes of non-biological drugs that have been tried in chronic lymphocytic leukemia patients with variable degrees of success.

IMIDs or immune modulating drugs:

Lenalidomide (Revlimid) and some related compounds, such as thalidomide, have shown significant activity in CLL trials but have largely been abandoned as newer drugs have proven easier to use with better response rates. Still, they have a beneficial role to play “off label” for some patients who have failed drugs such as ibrutinib or venetoclax.  Exactly how IMIDs work is far from clear, but besides their effects on the multiple aspects of the immune systems, they also have anti-angiogenic (they stop blood vessels from growing and this is what led to all the horrific birth defects associated with thalidomide use during pregnancy), anti-inflammatory and anti-proliferative effects.

Immune checkpoint inhibitors:

Checkpoint inhibitors are a Nobel Prize winning breakthrough in cancer care and in trials have had a benefit in Richter’s Syndrome, but have unfortunately shown little benefit in CLL trials.

Here is their story:

The immune system must differentiate between normal cells and abnormal invaders and mutants such as cancer cells. We want the immune system to leave the normal cells alone and just attack the malignant deviants.  To help focus the attack on the bad guys, our immune system uses checkpoints as signals that need to be turned off or on to start an immune response.

PD-1 is one such checkpoint protein on T cells. It acts as a type of off/on switch that helps keep the T cells from attacking cells in the body. It does this when it attaches to PD-L1. When PD-1 binds to PD-L1, it directs the T cell to leave the other cell alone. But some cancer cells have hijacked this system using large amounts of PD-L1 to helps themselves hide from an immune attack.

Drugs that target either PD-1 or PD-L1 can block this binding by the cancer cells and therefore unleash the immune response.

Let’s now switch to biologicals, drugs from living sources.

IVIG (intravenous immune globulins):

IVIG, while not strictly a drug to treat CLL, is a pooled blood product that contains large amounts of antibodies, specifically IGG, and is used to “borrow” a passive immune response to prevent or control infections for chronic lymphocytic leukemia patients who are both deficient in IGG and are getting sick too often. It is also sometime used to control certain autoimmune problems seen in CLL such as AIHA (auto-immune hemolytic anemia with destruction of our red blood cells) and ITP (immune thrombocytopenic purpura with platelet destruction).

Monoclonal antibodies (MABs):

MABs have revolutionized the treatment of cancers in general and CLL in particular. A monoclonal antibody, or MAB, is an antibody produced by a clone of cells that are all identical. When they are man-made and directed against a cancer, they are helpful targeted killers themselves or are very capable of aiding and abetting other anti-cancer treatments in the mass murder of the malignant clone.

In CLL, these monoclonal antibodies are already approved: rituximab, ofatumumab, obinutuzumab, and alemtuzumab.  More are in promising trials.

A newer subgroup of MABs is the bispecific antibodies discussed here in a separate review.


CAR-T (chimeric antigen receptor- T cell) and its cousin, CAR-NK (chimeric antigen receptor- natural killer cell) are experimental cellular therapies where cells are removed and then are genetically rewired to recognize and attack cancer cells by attaching to a surface maker on the CLL cells and killing it. We have extensive information on the impressive results for CAR-T therapy in clinical trials in CAR-T section of the website.

In summary, immune therapies make good on the promise of having a targeted therapy that work with, instead of against, the body’s own powerful immune system to control the cancer and minimize the collateral damage.

Move over, they are especially good at playing with others and when added into a treatment regime, often help new and old therapies provide deeper and more durable responses.

Immunotherapies are a big part of present and future of CLL treatment.

Stay strong. We are all in this together.

Brian Koffman, MDCM

EVP and CMO, CLL Society

Dr. Brian Koffman, a well-known retired doctor, educator, and clinical professor turned patient has dedicated himself to teaching and helping the CLL community since his diagnosis in 2005. He serves as the Executive Vice President and Chief Medical Officer of the CLL Society Inc.

Originally published in The CLL Society Tribune Q2 2020.