Dr. Tanja A. Gruber is division chief of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine at Stanford Medicine Children's Health.

Dr. Tanja A. Gruber

CAR-T cell therapy has cured some children with blood cancers and is being studied in solid tumors, where responses differ due to how these cancers grow.

What Is CAR-T Cell Therapy’s Role in Pediatric Solid Tumors?

CAR-T cell therapy has cured some children with blood cancers when chemotherapy could not, said Dr. Tanja Gruber of Stanford. By engineering a patient’s immune cells to target cancer, it offers a new approach distinct from chemotherapy.

Gruber explained that while early responses in solid tumors such as brain cancers are encouraging, they haven’t yet matched the rapid success seen in blood cancers, which circulate throughout the body and differ from tumors in specific locations.

Gruber is a physician-scientist specializing in pediatric blood cancers, with expertise in infants with leukemia and acute myeloid leukemia. She trained at USC and Children’s Hospital Los Angeles, served 11 years on the faculty at St. Jude, and is now chief of pediatric hematology, oncology, stem cell transplant and regenerative medicine at Stanford.

Can you talk about how CAR T, which began in blood cancers and is now moving into solid tumors, may impact pediatric patients and their families?

I'll start with saying how much it impacted children with blood cancers, and then go from there and how we see that transition or translation into the solid tumor world.

But in terms of blood cancers, what was really amazing is that CAR-T therapy was able to put patients in remission who were very resistant to chemotherapy, and so we were able to cure children that chemotherapy couldn’t cure. That was really a huge advance in our field.

The other thing we learned is that some of the things that may make a patient resistant to chemotherapy don’t necessarily make you resistant to CAR-T. That’s because it’s a very different way of killing the cancer cells. It’s really engineering a patient’s own immune cells to recognize and kill the cancer, which is very different from how chemotherapy works, which targets rapidly dividing cells.

We would then anticipate, of course, that if we have CAR-T cells for brain tumors or solid tumors, we would see a similar response. I would say we’ve seen some very encouraging responses, but it wasn’t the immediate home run that we saw for blood cancers. That’s because when you have brain tumors and solid tumors, it’s very different from a blood cancer, which is circulating all over your body and is a cancer of immune cells.

Transcript has been edited for clarity and conciseness.

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Videos

CURE sat down with Dr. Tanja A. Gruber of Stanford Medicine Children’s Health to discuss clinical trials in infant leukemia.

Treatment Advancements Bring Optimism in Infant Leukemia

Recent advancements have brought optimism when it comes to treating infant patients with leukemia, particularly those with acute lymphoblastic leukemia, or ALL, as one expert explained in an interview with CURE.

CURE sat down with Dr. Tanja A. Gruber, Division Chief of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine at Stanford Medicine Children's Health.

What are some current clinical trials that patients and their families should be aware of, particularly with regards to infant leukemia?

What we know from genetic studies on the tumor cells themselves is that the majority of these babies or infants have a very particular mutation that makes the leukemia cells resistant to standard chemo. We've actually been using a very standard chemotherapy regimen for the past 25 years, and we know that that treatment doesn't cure the majority of the infants.

So, what we did in my laboratory is we took samples. Patients' families were very generous and donated leftover leukemia cells from bone marrows that were done to diagnose the cancer. We took those cells and screened them with over 1,000 FDA-approved drugs to try and find drugs that were active against this leukemia that weren't being used. That was how we established the treatment regimen for the first study we conducted, called TINI, which stands for Total Therapy for Infants with ALL. We incorporated two drugs into the chemotherapy regimen that previously weren't being used. These drugs were being used for other types of cancers but not for infants with acute lymphoblastic leukemia. One of these drugs is a proteasome inhibitor called Velcade (bortezomib), and one drug is a histone deacetylase inhibitor called resminostat. What we found is that when we incorporated those medicines into the treatment, we were able to get a much lower disease burden.

After one cycle of chemo, we were able to get the leukemia down much better than with the standard chemotherapy that was being used for the first six weeks of treatment. We presented that at the American Society of Hematology meeting in December 2023, and the full paper is now under review, so we hope to publish it very soon. This now provides us with a more effective chemo on which to build from.

With this second trial, which is now open, we've activated at 10 sites across the U.S. and will have a total of 25 sites opening the study. The study builds on that chemo, and what we've done is we've added a type of immune-directed therapy called Blincyto (blinatumomab). What it does is it's an antibody, a molecule that recognizes the leukemia and then also brings one of the patient's own immune cells into proximity, and then the immune cell kills that leukemia cell. So, it's a type of immunotherapy, but it's not maybe as complex as CAR-T cell therapy because we have vials of it and can administer it to patients, and this drug has been shown to be very effective at improving outcomes for childhood acute lymphoblastic leukemia. What it's recognizing on the leukemia cells is a protein called CD19, which is also present on the infant acute lymphoblastic leukemia cells.

The other thing we're doing is there's a new drug which is very specific for leukemia cells that have that mutation that the infant leukemia patients have. We call that mutation a KMT2A rearrangement. Essentially, the drug is active against cells that have that KMT2A mutation but not against cells that don't. So what we're doing is we're incorporating this drug as well into the chemotherapy regimen for the babies. We're very excited. We've activated and are open to enrollment. We've already enrolled five patients, and we're very optimistic that this is going to improve the cure rates for these infants.

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CAR-T cell therapies are now being explored for the treatment of solid tumors like gliomas, Dr. Tanja A. Gruber explained in an interview with CURE.

CAR T Being Explored in Glioma Following Successes in Blood Cancer

After making strides in the treatment of blood cancers, innovative CAR-T cell therapies are now being explored for the treatment of solid tumors such as gliomas, an expert explained in an interview with CURE.

“We initiated trials where we introduced CAR-Ts into the brain for brain tumors, specifically for high-risk gliomas, diffuse midline gliomas and diffuse intrinsic pontine gliomas, and we learned that we were getting very nice responses, but we couldn't just give the CAR-T once, like we do for blood cancers. We had to give repeated doses of the CAR-T to sustain the response we were seeing,” explained Dr. Tanja A. Gruber.

Gruber, division chief of Pediatric Hematology, Oncology, Stem Cell Transplantation & Regenerative Medicine at Stanford Medicine Children's Health, spoke with CURE about the impact of CAR-T cell therapy and what is next for the transformative therapy.

How has CAR-T cell therapy impacted pediatric patients with blood cancers and solid tumors?

In terms of blood cancers, what was truly amazing is that CAR-T therapy was able to put patients into remission who were very resistant to chemotherapy. We were able to cure children that chemotherapy couldn't, which was a huge advance in our field. The other thing we learned is that some of the factors that might make a patient resistant to chemotherapy don't necessarily make them resistant to CAR-T. That's because CAR-T therapy is a very different way of killing cancer cells; it involves engineering a patient's own immune cells to recognize and kill the cancer, which is very different from how chemotherapy works, which targets rapidly dividing cells.

We would, of course, anticipate a similar response with CAR-T cells for brain tumors or solid tumors. While we have seen some very encouraging responses, it wasn't the immediate home run we saw for blood cancers. This is because brain tumors and solid tumors are very different from blood cancers. A blood cancer circulates all over the body and is a cancer of immune cells.

With solid tumors, you have what we call a microenvironment, meaning the tumor is located somewhere in your tissues as a mass, and there are a lot of immune cells present within that tumor. So, the CAR-T cells don't just have to recognize and kill the tumor; they also have to get around that microenvironment, which can sometimes create barriers that prevent a response.

Here at Stanford, we've learned a lot about CAR-T cells. We initiated trials where we introduced CAR-Ts into the brain for brain tumors, specifically for high-risk gliomas, diffuse midline gliomas, and diffuse intrinsic pontine gliomas. We learned that we were getting very nice responses, but we couldn't just give the CAR-T once, like we do for blood cancers. We had to give repeated doses of the CAR-T to sustain the response we were seeing, and that's because of the microenvironment. So, I think moving forward, the research is really going to be about asking, “How do we break down that barrier, or that resistance, to be able to give a CAR-T just once, for example?”

Dr. Tanja A. Gruber

What Is CAR-T Cell Therapy’s Role in Pediatric Solid Tumors?

Treatment Advancements Bring Optimism in Infant Leukemia

CAR T Being Explored in Glioma Following Successes in Blood Cancer

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