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• Newer targeted therapies under development for lymphoma may be more effective or have fewer or milder side effects compared with existing approaches.
• Antibody-drug conjugates are a newer approach to delivering anticancer drugs directly to cancer cells.
• Chimeric antigen receptor (CAR) T-cell and CAR-natural killer (NK) cell therapies seek to harness the body’s immune cells to identify and attack lymphoma cells.
• Other research is focused on blocking signals sent by oncogenes — abnormal genes that prompt healthy cells to become cancerous.

Rates of lymphoma have been rising for many years. While current treatment options can now offer the possibility of a cure for some types of lymphoma, other cases prove resistant to available therapies.

MyLymphomaTeam spoke with Dr. Robert Dean to find out about cutting-edge approaches that have recently been approved by the U.S Food and Drug Administration (FDA) to treat lymphoma or are still under development in clinical trials.

Dr. Dean is board-certified in medical oncology and hematology. He is a member of the department of hematology and medical oncology at the Cleveland Clinic Taussig Cancer Institute, and an assistant professor in the department of medicine at Case Western Reserve University.

Targeted therapies are a major focus of current research into new lymphoma treatments. How do targeted therapies work?

To understand what we’re talking about when we refer to targeted therapies in cancer treatment, it helps to understand a little about our original cancer treatments, what we call cytotoxic chemotherapy drugs. What most of these drugs have in common is their ability to attack and kill cancer cells, which spend more of their time in an active growth phase than most of the normal healthy tissues of our body. One of the problems with those drugs is that they also tend to have effects on other parts of the body where the tissues are actively growing, such as hair and bone marrow. This results in side effects like hair falling out, low blood counts, risk for infection, and other problems.

In contrast with those older chemotherapy drugs, targeted drugs for cancer work based on a more detailed, specific understanding of what changes have occurred in a normal cell to make it into a cancer cell. Targeted drugs try to attack what makes that cancer cell tick. The basic concept with targeted therapies is to make the effects of the drug attacking the cells more precise. We’re going after the target cells that we want to get rid of, while having less of an effect on the normal healthy cells in our body in the process.

Examples of Targeted Therapy

A good example of this in lymphoma is in the newer class of drugs called Bruton’s tyrosine kinase (BTK) inhibitors, which include Imbruvica (ibrutinib), Calquence (acalabrutinib), and Brukinsa (zanubrutinib). In some blood cancers that come from the antibody-producing white blood cells of the immune system called B cells, mutations activate a sort of internal relay system that turns the cell on and makes it grow abnormally. Bruton’s tyrosine kinase inhibitors work by blocking one of the switches in that signal system as a way of deactivating the cell and taking away that signal that tells it to grow.

Another form of targeted therapy works by recognizing a marker that’s present on the outside of cancer cells that most normal cells don’t have, and isolating the effects of the drug that you’re giving. One of the earliest examples of a targeted drug in cancer treatment was the engineered antibody drug Rituxan (rituximab), which recognizes a surface marker on most B-cell lymphoma cells. It’s injected, and when it finds a lymphoma cell, it attaches onto that marker and flags it for other healthy immune cells to come along and try to attack and destroy that tagged cell, just as if it were an invading infectious particle.

Is it correct to say that targeted therapies tend to have fewer or milder side effects compared with traditional chemotherapy?

Absolutely true. That’s one of the really exciting parts of the development of targeted drugs, in cancer medicine in general and certainly in the treatment of lymphomas. We now have drugs to treat various kinds of lymphoma that are in some cases more effective, or sometimes less toxic, and sometimes both more effective and less toxic than the earlier chemotherapy-based treatments.

Are targeted therapies replacing chemotherapy as lymphoma treatments?

Older chemotherapy drugs still have an important role in treating lymphoma. They can cure certain kinds of lymphoma and still remain a core part of our approach to treatment for a lot of patients. But as the research, development, and approval of targeted drugs have advanced over the last 15 years, we’ve had more options for patients who either have had their lymphomas relapse and needed new options, or who would not have tolerated our earlier chemotherapy treatments, but now have less toxic options available. Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an example of a lymphoma-related cancer where targeted drugs have largely replaced older chemotherapy approaches as the main forms of treatment.

What new targets are being identified in lymphoma?

In the last five years or so, there’s been a lot of research on another activation system in some lymphoma cells called the phosphoinositide 3-kinase (PI3K) pathway. We now have three different PI3K drugs on the market approved to treat low-grade B-cell lymphomas. There are also newer versions of these drugs being developed in clinical trials that are either potentially more effective, or possibly have a more favorable set of side effects than some of those currently available.

Researchers have also recognized the importance of apoptosis, a “fail-safe” system that kicks in and makes a damaged cell shut down and die. In many forms of lymphoma, a survival signal turns on abnormally and overrides that fail-safe system, allowing the cancer cells to survive and continue to grow under circumstances where most normal cells could not. This survival signal is often controlled by a cell protein called BCL-2. There’s a highly effective BCL-2 inhibitor, or drug for blocking that signal, called Venclexta (venetoclax), as well as second-generation drugs that also work at blocking that signal. Venetoclax is currently approved for treating some cases of CLL/SLL and acute myelogenous leukemia (AML), but also has shown activity in mantle cell lymphoma.

Are these new targeted therapies available now in clinical trials?

Some of them are approved and part of our standard practice now for some types of lymphomas, and are being investigated in clinical trials to determine whether they’re helpful in other situations.

For example, we’ve been exploring the potential use of venetoclax to make resistant lymphoma cells more sensitive to the effects of chemotherapy in high-risk patients. We’ve been testing it in clinical trials in combination with chemotherapy regimens such as RICE, or the high-dose chemotherapy treatment known as BEAM with stem cell transplantation. We’re trying to find safe combinations that can help improve the odds of patients maintaining remission over time.

What are antibody-drug conjugates?

Antibody-drug conjugates are a means of directing the effects of a chemotherapy-based treatment in a more selective way. The original approach was to give those kinds of chemotherapy drugs in a way that would work throughout the entire system. An antibody-drug conjugate hooks a cytotoxic drug onto an antibody as a carrier to piggyback that chemotherapy-based drug in a more selective and direct manner to cancer cells. Think of it as a cancer treatment “smart bomb” that uses an antibody to guide a drug to its target.

For example, in the treatment of Hodgkin lymphoma, the cancerous cells have on their surface a marker that is known as CD30. There are genetically engineered antibodies that can recognize that marker. If you attach a molecule of an anticancer drug to that antibody and give it intravenously, then that antibody will go throughout the bloodstream and tissues, and when it encounters one of these cancer cells, it will attach to it, enter the cell, and paralyze the cell, causing it to die. Drugs that work this way include Adcetris (brentuximab vedotin), which is approved for the treatment of most cases of Hodgkin lymphoma.

Which are currently approved for lymphoma, and are there any new treatments in development?

We have an approved antibody-drug conjugate now for aggressive non-Hodgkin lymphoma (NHL) called Polivy (polatuzumab vedotin-piiq). A number of other antibody-drug conjugates are undergoing testing in clinical trials right now, including for both Hodgkin and non-Hodgkin lymphomas.

There has been a lot of discussion recently about CAR-T cell therapy. How does it work, and how promising is it for treating lymphoma?

We’re really excited about the developments in CAR-T cell therapy. It has really been a practice-changing development for us and for our patients, because it offers a chance of cure for some patients whose lymphomas cannot be cured by any other treatment. CAR-T cell therapy is another form of targeted therapy, and also a kind of immunotherapy, which harnesses your immune system to attack cancers.

The Traditional Approach: Intensive Chemotherapy

In aggressive forms of lymphoma that relapse in spite of traditional chemotherapy treatment, we use a course of very intensive chemotherapy to try to destroy any residual lymphoma cells, and a stem cell transplant to get the bone marrow back online and functioning normally. The problem is that intensive treatment still doesn’t work for everybody. A significant proportion of patients relapse.

T Cells Recognize and Destroy Infected Cells

CAR-T cell therapies use someone’s own healthy, mature immune cells to try to eradicate resistant lymphoma cells instead of having to rely on a super-powerful chemotherapy treatment. In some ways, CAR-T cell treatment looks similar to a stem cell transplant. For both processes, you collect cells out of the patient’s blood and store them, then give them back later after some chemotherapy. With CAR-T cell therapy, the cells that you take out aren’t the primitive bone marrow stem cells that can produce all the different cells of the blood. Instead, you’re going after mature immune cells called T cells. In their natural state, T cells recognize when a cell has become infected with a foreign particle like a virus and destroys that cell.

Engineered To Attack Cancer Cells

CAR-T cell therapy takes T cells out of the body and reprograms them using genetic engineering techniques to recognize a marker on cancer cells. Then those engineered T cells are reintroduced into the body and encouraged to grow and attack resistant lymphoma cells. Some chemotherapy is given beforehand to perform a reset of the immune system and create growth factors that turn the T cells on to make them more likely to recognize and attack the target lymphoma cells.

CAR-T Cell Therapy for Lymphoma and Leukemia

Three different CAR-T cell therapy treatments have now been approved for patients with aggressive NHL. CAR-T cell therapies have also been approved for the treatment of:

	Aggressive immature lymphoid leukemia
	Acute lymphoblastic leukemia (ALL) in younger patients up to the age of 25
	Relapsed and resistant mantle cell lymphoma
	Resistant low-grade follicular lymphoma

Studies are ongoing for CAR-T cell therapies in other low-grade lymphomas, CLL/SLL, and other diseases.

Is CAR-NK cell therapy similar to CAR-T cell therapy?

The immune system has many different immune cells that could potentially recognize a cancerous cell and attack to try and destroy it. T cells have to be activated by a target cell or a target infection before they can begin to respond. Natural killer cells are capable of instantaneously recognizing things that are abnormal in the body, and trying to attack and eliminate them without having to go through previous exposure or training.

NK cell therapy has been under investigation for probably 15 years or longer, particularly in the context of bone marrow and stem cell transplant, when we’re trying to eliminate residual cancer cells. Now that we’ve seen these successes with engineering T cells for treating resistant blood cancers like lymphomas, there’s a lot of effort underway to explore the potential of other immune cells, such as natural killer cells.

Potential Advantages of CAR-NK Cell Treatment

One advantage of CAR-NK cell treatment is the ability to produce them from the white blood cells of a healthy, unrelated blood donor, without having to match the donor to the patient in the same way that is required for bone marrow transplantation. This makes it possible to prepare CAR-NK cells in advance, so that they are available as soon as they are needed. That’s an important difference from the currently available CAR-T cell treatments, which are produced from a patient’s own T cells in a process that can take a few weeks. That waiting period can be an important obstacle for a patient with rapidly growing, chemotherapy-resistant lymphoma. The early results for a study of donor-derived CAR-NK cell therapy in lymphoma patients are promising, with encouraging rates of remission and relatively mild side effects compared with CAR-T cell therapy.

What are oncogenes, and how can targeting them help treat lymphoma?

Oncogenes are the genetic basis for the abnormal signals that make cells grow out of control and behave like cancer cells. In our bodies, millions of normal cells quietly do their work the way they’re supposed to without making a mistake. There are a lot of safety features built into our cells that keep them from growing out of control and turning into cancer.

Critical functions of our cells that are tightly controlled by genes include:

	When cells grow, and when they stop growing
	When they die naturally
	When and how they’re allowed to move throughout the body
	How much energy they’re supposed to be using
	Sensing and repairing damage to the cell’s genes
	When cells can avoid being recognized and attacked by the immune system

These safety features have to break down or go offline in order for a cell to change from being a normal cell to a cancer cell. It took decades of research into the basic biology of cancers to understand what genes control those functions and how they varied from one form of cancer to another.

In almost every form of cancer, changes in specific genes that we call oncogenes are at the root of how those functions of the cell change. In some cases, they’re like stepping on the gas pedal. In aggressive lymphomas like Burkitt lymphoma and diffuse large B-cell lymphoma, a gene with this function can be turned on in an uncontrolled manner and left running all the time. Right now, there are drugs in clinical trials that we hope can block that activation signal — taking the foot off the gas pedal. In other cases, cancer cells change in ways that turn off oncogenes that normally act like a brake pedal, so the result is like a runaway train.

Talk With Others Who Understand

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