Upward and onward with new CAR-T Cell Cancer therapy

CANCER  BREAKTHROUGH: CAR – T CELL THERAPY

Cancer ranks as the most feared disease stirring memories of suffering, pain and  disability followed by a lengthy downward spiral to death.  Traditional approaches include surgery, radiation and chemotherapy.  While still evolving into the modern era, these options unfortunately offer limited success.  Newer targeted therapies with drugs including Gleevec, Herceptin and Opdivo provide major a advance but still leave considerable room for improvement.

Enter the cancer breakthrough CAR-T Cell Therapy capable of directing the body’s immune system at malignant cells previously unable to be destroyed.  Considered as “breakthrough therapy” by the Food and Drug Administration, the initial two agents received priority review followed by marketing approval within less than one year.  Kymriah received FDA blessing on August 30, 2017 with Yescarta following six weeks later.

HISTORY

Harnessing the immune system to combat disease originated in the late 1890s with attempts to treat cancer.  Due to lack of sophisticated technology and only rudimentary knowledge, the concept matured slowly.  In the late 1980s an Israeli scientist Dr. Eshhar working at the Weizmann Institute pioneered the idea of combining portions of animal cells with human cells to direct an immune attack.  A dramatic revolutionary new form of cancer therapy evolved Through his subsequent work at the National Cancer Institute with Dr. Stephen Rosenberg with the addition of Dr. Carl June from the University of Pennsylvania.

As testimony to the importance of this novel therapy, less than ten years ago only a handful of centers were studying the technique.  That number has exploded to include over 500 different trials.  Sensing long term benefits of this approach, within the past year the company behind one of the therapies was purchased for almost $12 billion.

With only preliminary statistics testifying to survival, the outcome seems extraordinarily impressive.  Realizing that patients eligible for treatment failed at least two courses of currently standard therapy and were basically consigned to hospice care or death, CAR T-Cell therapy provided complete remission / cure of the disease in 50 – 80% of patients.  Unfortunately some relapses occurred, however at the latest follow-up approximately 50% of treated patients still appear cured without any evidence of active disease.

ACUTE LYMPHOBLASTIC LEUKEMIA OR ALL

Acute Lymphoblastic Leukemia or ALL, principally a childhood disease, was previously uniformly fatal.  With current chemotherapy and stem cell transplants, most children achieve a cure.  For those who relapse or fail to respond, little hope existed.

In 2010 Emily Whitehead received the diagnosis of ALL and initially appeared respond favorably to traditional therapy, although she suffered significant complications.  Unfortunately her disease relapsed within less than 18 months after a second round of therapy.  Without any novel treatment, hospice care and death seemed almost certain.  Fortunately Emily happened to be at the proverbial right place at the right time.

Dr. Carl June and his staff at Children’s Hospital of Philadelphia had been perfecting CAR T-Cell therapy for some time.  His journey catapulted forward when his wife developed ovarian cancer and eventually succumbed several years later.  Through perseverance and good fortune Dr. June navigated the scientific and financial hurdles to a point where their new treatment was ready for human investigation.  And that’s exactly when Emily appeared.

Emily became the first human treated with CAR T-Cell therapy and within weeks traveled from death’s doorstep to demonstrating no trace of leukemia. Her roller coaster journey unfolded: uncharted and quite rocky but trailblazing and amazingly successful.  Her treatment in April, 2012 signaled a new chapter in cancer therapy that will continue to evolve as it undergoes further refinements over the next several years to decades.

IMMUNE CELLS

Rather than a solitary disease, cancer represents a large number of conditions with varying clinical significance.  Malignancies may arise in the blood as in leukemia/ lymphoma or in solid tissues – breast, colon, prostate.  Some indolent or slow growing tumors never progress to a point that requires therapy.  They appear restrained either by their own genetic mutations or the body’s immune system prevents their uncontrolled growth.

The immune system functions by recognizing tiny molecules known as antigens on the surface of malignant cells.  Under ideal circumstances when the immune system becomes aware of these “foreign” cells, a specialized variety of white blood cell, helper T lymphocytes, surrounds the alien tissue and summons yet another subtype of T cells, the cytotoxic T cells, to kill or destroy their prey.  In the process these T cells along with other related immune cells produce a variety of chemical signals or cytokines that assist in communication amongst the army of cells as they maintain the attack.

T CELLS

These aggressive T cells displaying their receptors constantly search for antigens on the surface of tumor cells that do not belong in the body.  When the T cells discover a “non-self” or “foreign” antigen on a cancer cell, their external receptor connects with the antigen on the cancer cell and the battle begins.  This constitutes immunosurveillance.

In the case of ALL the malignant cell, in this case another subtype of lymphocytes known as B cells, displays a particular marker or antigen on its surface.  This compound known as CD-19 actually appears on all B cells, both malignant and healthy.  Since the normal immune cells interpret CD-19 as belonging in the body, they fail to attack and allow proliferation of both normal and leukemic cells.

B CELLS

Under normal circumstances B cells manufacture antibodies that ward off bacteria.  Obviously removing all of the B cells would lead to severe, perhaps fatal, bacterial infection.  Fortunately injections of gamma globulin intravenously generally suffice to prevent infection until reemergence of normal B cells in the aftermath of therapy.

CAR T – CELLS

So how does all of this relate to CAR-T Cell therapy?  CAR is short for Chimeric Antigen Receptor.  In the laboratory T cells can be infected with viruses loaded with snippets from mouse genes that allow them to recognize the CD-19 studding all of the B cells: both normal and leukemic.  When the process is successful, the body is cleared of all B cells and the patient is cured.

PROCESS

Now the details.  In a process known as leukapheresis, blood is drawn from the patient in a fashion similar to blood donation.  In this case however only the white blood cells are kept; the red cells, platelets and plasma are returned.  The white cells may be further concentrated to enrich the number of T cells after which the material is frozen and shipped to a specialized central laboratory.

Once the cells reach their destination, they are thawed and infected with genetically engineered viral particles carrying the genetic instructions.  These T cells not only manufacture the specialized antigen which ultimately appears on the cell surface, but they also receive instructions to synthesize a series of stimulatory and co-stimulatory substances positioned both within the cell and sitting astride the cell wall.  These stimulatory and co-stimulatory materials amplify the T cell’s ability to direct its cell killing material after attachment of the antigen to the receptor within the patient.

Afterward but still in the laboratory these newly armed T cells receive signals to multiply and continue to expand until they reach numbers in the hundreds of millions or billions.  These CAR T-Cells are then frozen and ready to be sent back to the hospital caring for the patient.

PATIENT PREPARATION AND THERAPY

Several days prior to receiving therapy, the patient returns to the hospital and undergoes a form of chemotherapy designed to destroy as many lymphocytes as possible – lymphocyte depletion therapy.  Generally this requires several days and begins about 5 days prior to the actual treatment.  This prepares the body to accept the CAR T-Cells.  The CAR T-Cells are thawed up to 30 minutes before infusion.  The patient receives premedication with anti-histamines and acetaminophen.

Intravenous therapy requires only about 30 minutes with only a single session.  Since these cells are alive they continue to multiply in the body over a period of at least several weeks to months with some remaining on patrol over a much longer interval – perhaps years.

ACTION IN THE BODY

When these special T cells with their genetically engineered receptors and primed stimulatory factors meet target cells displaying the appropriate surface CD-19 antigen, they react with reckless abandon and precision unlike typical chemotherapy.

Once attached to their prey, the surface receptor on the CAR T-Cells passes a signal through the engineered transmembrane stimulatory factor to its internal co-stimulatory material.  In turn this amplifies release of cytotoxic killing substances that are injected right into the cancer cell.

SIDE EFFECTS

Side effects pose substantial problems and may result in patient death.  Since the  normal antibody producing B cells are also destroyed, serious infection remains a constant threat.  The presence of active infection requires postponing CAR T-Cell therapy until the microbial invader no longer exists.  Unfortunately even with intravenous gamma globulin, 1 in 3 patients still experience a severe infection most typically from a bacteria or virus with many of undetermined origin.  Those carrying the hepatitis B virus from a prior infection may experience fulminant hepatitis at times culminating in liver failure.

CYTOKINE STORM

Exuberant cytokine production during the cancer cell-CAR T-Cell interaction regularly leads to a potentially life-threatening condition referred to as the Cytokine Release Syndrome or Cytokine Storm.  Mild cases exist and may be adequately treated with anti-histamines, aspirin, naproxen, opioids and intravenous fluids.  Unfortunately rapid deterioration often occurs within minutes precipitating a critical medical emergency.  As a result, hospitalization for at least 1 week after therapy remains mandatory.

Symptoms of Cytokine Release Syndrome include extremely high fever, a dramatic decline in blood pressure, striking elevation in heart rate, shortness of breath at times requiring mechanical ventilation and severe muscle, joint and abdominal pain.  Other manifestations include headache, confusion, loss of coordination, hallucinations, delirium and seizures.

Fortuitously the central mediator of the Cytokine Release Syndrome appears to be a substance known as IL-6.  And better yet, Actemra, a drug originally purposed to treat rheumatoid arthritis, exists to combat excessive amounts of this chemical.  Due to the nature of the Cytokine Storm, hospitals providing CAR T-Cell therapy are required to have sufficient quantity for at least 2 courses of therapy present in their pharmacy.  With Actemra at times coupled with high dose steroids most patients respond within a week.

OTHER SIDE EFFECTS

Other major adverse reactions with symptoms partially overlapping with Cytokine Storm may prove just as serious.  Neurological toxicity affects most patients with 1 in 3 suffering severe reactions that appear several days following therapy and typically persist for 2-3 weeks or longer.

Symptoms of central nervous system dysfunction include headache, tremor, dizziness, anxiety and tremor.  Some patients experience difficulty speaking, delirium or non-specific encephalopathy combined with seizures.  Swelling of the brain, cerebral edema, may result in death.  Supportive treatment provides a bridge until normal brain function returns.

While CAR T-Cell therapy specifically targets a unique antigen on the surface of the malignant cell, sometimes confusion exists when non-tumor cells express the same flag.  This leads to the “on tumor/off target” reaction that manifests as toxicity within the intestines, lungs or other blood cells.

Hypersensitivity reactions, allergies and anaphylaxis remain constant threats.  Long term reactions include heart dysfunction, kidney failure and liver disease.

NOT FOR EVERY HOSPITAL

With this long list of very serious and frequent side effects, CAR T-Cell therapy is currently restricted to patients who have failed to respond to at least 2 different forms of therapy and for whom no other salvage options exist.   Before CAR T-Cells the situation remained bleak and somewhat reminiscent of the inscription on the gates of hell in Dante’s Inferno Canto III:  “Abandon all hope, ye who enter here.”  Now the complete response rate – cure – appears likely in at least 50% of these individuals.

As CAR T-Cell therapy debuts in clinical practice, restrictions limit the number of facilities offering it to less than 30 major cancer centers and then only after intensive training regarding how to deal with the complications.  Over time a greater number of hospitals will expand availability, however this treatment is not meant for every local health care institution.

WHICH TYPES OF CANCERS?

At present malignancies of blood elements remain the primary focus of CAR T-Cell therapy.  And then only after failure to respond to several standard courses of therapy.  Anticipated candidates with acute lymphoblastic leukemia number no more than 600 each year with an additional 3000 people with a type of Non-Hodgkin’s lymphoma.  In the near future this treatment seems poised to gain FDA acceptance for treatment of Multiple Myeloma.

All of these malignancies demonstrate peculiarities of their surface antigens that allow relatively easy targeting by CAR T-Cells.  A much more difficult situation exists with solid tumors in the breast, lung, colon and prostate.  Although some of these tumors contain relatively unique surface antigens, the tumors create an external shield protecting them from immune assault.  Additionally many of the targets remain within rather than on the surface of the cancer cells.  In spite of this, progress is underway to modify CAR T-Cell therapy to challenge the tumors on their home turf.  Work is currently ongoing with the malignant brain tumor glioblastoma as well as prostate, ovary, breast and colon cancer among others.

CONTINUALLY EVOLVING THERAPY

Even though CAR T-Cell therapy remains in its infancy, it continues to change.  At first only one stimulatory factor was engineered into the cells, but the cancer killing response lacked the necessary gusto.  Adding a co-stimulator ramped up the cytotoxic response and proved considerably more beneficial.  More recently further alterations of the cells may have added greater potential in counteracting cancer.

At this time cells must be harvested from the specific patient and sent to the central laboratory for processing before being returned only to treat only the individual from whom they originated.  This delays treatment of these critically ill individuals and adds anywhere between one to two weeks or even longer to the process.  Some investigators are studying a less patient specific approach where the armed cells can be manufactured in advance and ready for anyone with the specific identifying antigenic tumor markers.

Interestingly tumors may mutate over time and lose the capacity to manufacture the specific antigens necessary for CAR T-Cell recognition.  This phenomenon appears responsible for some of the late tumor relapses even after apparently successful treatment.  In order to minimize the potential for tumors to evade the CAR T-Cells, researchers are investigating placing two rather than one specific recognition site on the T-cells.  This is akin to the prescription of multiple drugs for simultaneous use in treating pain, HIV, cancer and some infections.

FINAL THOUGHT

Another major impediment to widespread availability revolves around finances.  At this time the cost of a single unit of Kymriah for ALL is $475,000 while Yescarta for Non-Hodgkin’s lymphoma costs $373,000.  These prices include only the medication.  Adding hospital and related costs which generally include time in intensive care raises the estimated total amount to well in excess of $1 million.  Society cannot sustain such transfers of capital from the federal treasury or private insurance companies to either Gilead Sciences or Novartis.  Something has to give.  And oh, by the way, Dr. June was once quoted as saying the cost of processing was less than $20,000.

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