Chimeric Antigen Receptor T-cell Therapy: Harnessing the Body’s Immune System to Fight Cancer

New molecules and ways to effectively fight lymphomas are constantly being explored. One such approach is immuno-oncology which uses immunotherapies to treat cancer. Immuno-oncology refers to the use of the patient’s immune system to fight the patient’s cancer.

“By immunotherapies I mean treatments that mimic the body’s immune system,” said Dr. Stephen Schuster, Director, Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA.

An example of an immunotherapy approach is vaccines.

“When we vaccinate a patient, the patient’s immune system develops antibodies for which they have been vaccinated, the antibodies will neutralise that pathogen and the patient won’t become infected,” he said.

One of the earliest approaches to immuno-oncology was the development of monoclonal antibodies. Rituximab was the first approved anti-CD20 monoclonal antibody. Rituximab binds to CD20, a protein found on B cells, resulting in the killing of cancer cells.

“Subsequently, two other anti-CD20 monoclonal antibodies have been approved; namely, ofatumumab and obinutumumab both for chronic lymphocytic leukaemia,” he said.

 

Chimeric Antigen Receptor (CAR) T-cell Therapy

Another approach in the development of immunotherapies is the use of cellular immunity with T cells. Cellular immunity, also called cell-mediated immunity, is the response of the body’s immune system to harmful invading foreign organisms. The purpose of the cellular response is to kill the foreign organism.

“The earliest application of T cells was in the allotransplant setting where donor lymphocytes were used for the treatment of relapsed leukaemias. It was observed that donor lymphocyte T cells could put patients who were relapsing into remission,” said Dr. Schuster.

An autologous form of cellular immunotherapy – chimeric antigen receptor (CAR) T-cell therapy – is currently under investigation. There are a number of immunotherapy approaches but this article will focus on CART T-cell therapy specifically. 

“These cells are engineered to react against CD19 which is on the surface of B cells. They direct the cellular immune system to the disease sites and eliminate the cancer cells,” he said. 

 

Process for Generating CAR T Cells

The following steps outline the process for developing CAR T cells:

  1. White blood cells that include T cells are removed from the patient’s body through a process called leukapheresis.
  2. The white blood cells along with the T cells are then sent to a laboratory where they are genetically modified or manipulated to react against CD19. This is achieved by programming the genes with the CAR using an inactive virus called a viral vector.
  3. After 12 to 14 days, the cultured cells are harvested.
  4. Prior to the patient being infused with the harvested CAR T cells, they may receive lymphodepleting chemotherapy to reduce the level of white blood cells and help the body accept the reprogrammed T cells.
  5. The harvested reprogrammed T cells are infused into the patient in an outpatient setting. Once the reprogrammed T cells are infused into the patient’s body, they expand and start looking for cancer cells that express CD19. Once found, the reprogrammed T cells attach to the CD19-expressing cells and start to kill them.1,2

 

Clinical Trials Examining CAR T-cell Therapy

A number of clinical trials have examined the use of CAR T-cell therapy. One such agent is CTL019, a CAR-modified T-cell therapy that reacts against CD19. The use of CTL019 has been studied in diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and follicular lymphoma (FL).3

“We saw activity in all three histologies. The largest number of patients treated to date are those with DLBCL. Basically, we were able to induce remission in those patients at least half the time and those responses are durable as far as two years now with a single treatment,” said Dr. Schuster. He has treated 13 patients with DLBCL. In FL, Dr. Shuster said response rates have been in excess of 80%.

“With MCL, we’ve only treated a couple of patients. In those we have treated, we did see activity. We need to accrue more patients but are waiting for funding,” he said.

In total, Dr. Schuster said he has treated 29 patients with CAR T-cell therapy. Globally, he estimated that more than 100 patients with different lymphomas have been treated with this form of therapy.

At the University of Pennsylvania alone, Dr. Schuster said more than 200 patients had been treated with CAR T-cell therapy when factoring in the patients with acute lymphocytic leukaemia as well as those with lymphoma.

“Having now two years of hands-on experience with this treatment approach, I can say it is active in patients who would probably otherwise not have any reasonable treatment options,” he said.

A multicentre, long-term follow-up study of patients who have been exposed to CAR T-cell therapy is currently underway.4 This study will monitor all patients who have received CAR T-cell therapy for 15 years to determine if they experience any adverse events, monitor for replication competent lentivirus and assess long-term efficacy.

While CTL019 is the most advanced of the CAR T-cell therapies under investigation, there are other ones being studied.

“You can make a CAR cell that targets any antigen you want. People are studying CARs against CD20. We have one against CD22 which is going to go into testing,” he said.

 

Safety Issues with CAR T-cell Therapy

CAR T-cell therapy is associated with some unique toxicities one of which is cytokine release syndrome. Cytokine release syndrome occurs as a result of a reaction to the infusion. When a large number of T cells are infused into the body, they release cytokines. This may cause fevers and a drop in blood pressure that may require treatment to be stopped.2

“The other toxicity is neurotoxicity. It is generally transient lasting a few days and tends to resolve,” said Dr. Schuster.

Dr. Schuster noted that treatment with CAR T cells is done on an outpatient basis.

“Half of my patients never get admitted to the hospital. If they have a fever, I admit them,” he said.

 

CAR T-cell Therapy’s Place in Treatment

Dr. Schuster sees CAR T-cell therapy being of value to patients who do not have a good prognosis such as those who relapse within a year of their primary treatment, those not responding to salvage chemotherapy and those with positive scans of residual disease at the outset. The use of CAR T-cell therapy has been studied in three lymphoma subtypes; namely DLBCL, FL and MCL.

“If CAR T-cell therapy is available and even in those who fail transplant, we’ve had success in 50% of cases and it’s a lot easier treatment,” said Dr. Schuster.

He noted that in patients who have a recurrence within a year of their rituximab-based treatment or in those who have received an autotransplant, only 20% of them will be successfully treated. 

 

Addressing Patient Concerns

Many patients and patient organisations are concerned about the implications that a therapeutic approach like immuno-oncology might have on their immune system.

“One of the biggest obstacles to using this form of therapy is that most of our conventional lymphoma therapies deplete the body’s immune system cells and lymphocytes as effectively, if not more effectively, than they eliminate cancer. In this process, we’re also killing normal lymphocytes,” said Dr. Schuster.

For a number of patients, especially those with B-cell lymphomas who have been heavily pretreated, no therapy has been available for them because their immune system is so damaged.

“I think all this will start to change as the technology becomes better understood and available. Physicians are going to be more cognisant of the need to preserve the immune system so if we need to use this form of therapy we can,” he said.

Dr. Schuster went on to say that patients with a bad prognosis should consider having a sample of their T cells collected before starting treatment, or even early in their treatment. In the event that their initially prescribed therapy is unsuccessful, they then have a treatment option available to them.

Having new treatment options for patients with B-cell lymphomas who are at a high risk of relapse is imperative. While CAR T-cell therapy shows promise, more research is needed to substantiate these early promising results as well as answer questions such as what the long-term implications are on altering the immune system and what impact these alterations will have on other organs in the body.

As more information becomes available on CAR T-cell therapy and other immunotherapies, the Lymphoma Coalition will provide updates.

 

References

  1. Mato A et al. Blood 2015;126:478-85.
  2. Iarocci T. Lymphoma Hub http://lymphoma.about.com/od/treatment/fl/CAR-T-Cell-Therapy-Spurs-Optimism.htm Accessed December 1, 2015.
  3. Schuster SJ et al. Hematol Oncol 2015;33:100-80.
  4. Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT02445222?term=CTL019&rank=6. Accessed November 30, 2015.

 

Author: Leonie Bedford, Medical Writer, Lymphoma Coalition

January 25, 2016

 

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