The CAR-T therapies (Chimeric Antigen T-cell Receptor) have become one of the great advances in the treatment of hematological cancer. Immunotherapy has represented a new paradigm for patients who have a complicated prognosis “where traditional therapies do not work and in fact they were approved first in those with refractory disease.”
He Dr. Miguel Ángel Peralesa bone marrow transplant and cell therapy specialist at Memorial Sloan Kettering Hospital in New York, explains to ‘Health Guides’that “we are seeing responses in patients with diseases refractory to classic treatments and, with the follow-up of more than 10 years that we already have in some cases, we can talk about cure”.
An example of this is “patients with diffuse large cell lymphoma, we can consider that we are curing around 30 to 40% of the patients.” And, although “it is lower than one would expect, but we must also take into account that they are patients with refractory disease”.
In this type of hematological cancer, CAR-T therapies are used in the second line, when the initial treatment is not effective, “we could also consider using CAR-T cells in the first line in cases of very high risk of relapse.”
What is CAR-T treatment?
CAR-T cell treatment is a cellular immunotherapy procedure that is indicated for some types of hematological cancers, it has proven effective in patients with certain types of leukemias, lymphomas and myelomas.
CAR-T immunotherapy is, without a doubt, the most revolutionized in the world of cancer. But how does CAR-T cell treatment work?
T lymphocytes, which are immune system cells formed from stem cells in the bone marrow, are used to genetically modify them so that they can destroy tumor cells.
This therapy achieves long-lasting remissions in many patients with hematological cancer. However, side effects can also occur, such as neurological effects that affect speech, tremors, delirium, and seizures.
Will it put an end to the traditional bone marrow transplant?
Dr. Perales points out that “I don’t know if we can say that it will end the traditional bone marrow transplantbut in the United States and Europe we are seeing a significant decrease in the use of autologous transplantation and even more allogeneic transplantation in patients with diffuse large cell lymphoma.”
However, one of the handicaps that immunotherapy faces is its high price. “In the United States we did a study of profitability of Yescarta in second line based on the results of the phase 3 ZUMA-7 trial and in that case we can demonstrate that the results are positive in favor of CAR-T compared to treatment with traditional bone marrow transplant.”
“This type of analysis would have to be confirmed in other health systems such as in Spain, for example. Another option that also seems interesting to me is the academic CAR-T where Spain is the world leader in my opinion. “Allogeneic CAR-T could be a cheaper option, since it costs less to produce the cells in that case.”
Why don’t CAR-Ts work in some patients?
Age is not a limitation for CAR-T treatments, as some studies have shown. “We also know that in ZUMA-7, for example, the results in patients over 65 years of age are similar to those of younger patients“, highlights the specialist.
But, the more difficult question is why there are still patients who are resistant to CAR-T cells. “This is still a fairly difficult patient population to treat as we published, showing that overall survival is quite low in these patients.”
However, “the good news is that today we have new treatments such as bi-specific antibodies that we can consider for these patients and we also continue to have the option of an allogeneic transplant.”
New challenges of CAR-T therapy: going for solid tumors
There are several trials in solid tumors and some with “quite promising” results, even in tumors with very few other options. In the United States” we have approval of another cell therapy in patients with melanomawhat we call TILs, or lymphocytes infiltrating the tumor.”
“These cells are not genetically modified like CAR T cells. But there are clinical trials where TILs are being modified to increase their potency. Finally, I think we will see the first approval of a TCR T cell therapy for patients with sarcoma before the end of the year in the United States.”
And as to whether there is a danger of side effects, after the FDA issued a warning of “serious risk” of T cell malignancy in patients treated with CAR-T, oncologist Perales emphasizes that “in most cases we do not have proves that lymphoma is in CAR-T cells and in fact in some cases lymphoma has no relationship with the modified cells.
“We also have to remember that the highest risk of secondary neoplasms is myelodysplastic syndrome or acute leukemia, where it is difficult to say if it is the cells or the chemotherapy and sometimes radiotherapy that the patient has already received.”
But, “I have no doubt that in some cases there is a direct relationship and it is something that we have to be aware of.” The doctor highlights that “it is important to remember that This complication is very, very rare. and that we are talking about treatments for patients with refractory lymphoma or myeloma where the risk of death from the disease is much higher than this side effect.”
In any case, the doctor tells us that “I have no doubt in continuing to recommend this treatment to my patients, explaining the risks as we always do.”
How are CAR-Ts addressed in the United States and Spain? What differences are there?
The larger differences that “we see in CAR-T treatment between the United States and Spain are due more to differences in approval or reimbursement of these advanced therapies.” “For example, we have been using CAR-T in the second line for diffuse large cell lymphoma since the beginning of 2022 and in Spain it has only just been approved in this line. In our center, the majority of the patients that I see today for CAR T in that indication are second-line patients. There are also obviously differences in the type of health system and consequences that we see in access to advanced therapies.” Now that second-line CAR-T is approved in Spain, it will be important to “ensure that all eligible patients have access.”
Dr. Miguel Ángel Perales has been working at Memorial Sloan Kettering for more than 25 years and has been able to see first-hand the evolution of the CAR T program since it began in the late 90s. “At that time There was a lot of skepticism not only for immunotherapy in general, but also for the future of CAR-T cells. I remember colleagues who told Renier Brentjens, who at that time was working in Michel Sadelain’s laboratory, that there was no future in this type of treatment and that he would better dedicate himself to another project.
Now the question of where we will be in 20 years. “I hope that we can treat cancer patients without chemotherapy and radiation, with more specific treatments against the mutations we see in cancer, and perhaps get to the point where we can diagnose patients before they have cancer and intervene to prevent the development of cancer.”
Where are we going to be with cell therapy in the next 4 or 5 years? “I think we’re going to see further development of CAR-T cells in patients with tumors hematologicalsolid tumors, and especially in autoimmune diseases, where we are now seeing a lot of interest and some very promising results.”