Targeting Immunotherapies for Hematologic Malignancies

Guenther Koehne, MD

In the rapidly evolving landscape of hematologic malignancies, immunotherapies are ushering in transformative shifts in treatment approaches. Guenther Koehne, MD, shed light on these advancements, emphasizing the current focus on immunotherapies for conditions like multiple myeloma, leukemia, and lymphoma.

Three key categories stand out in this paradigm shift: Chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody-drug conjugates.

CAR T cells, established through labor-intensive processes, involve modifying a patient's T cells for specific marker expression, targeting malignant cells. Bispecific antibodies, readily available off-the-shelf, facilitateT-cell interaction with tumor cells. Antibody-drug conjugates deploy antibodies, targeting tumor cells with integrated toxinsand inducing tumor cell death. The challenge lies in determining the most effective approach and transitioning from monotherapy to combination therapies.

While acknowledging the effectiveness of immunotherapies, Koehne, deputy director and chief of blood and marrow transplantation and immunotherapies, hematologic oncology, of the Miami Cancer Institute, Baptist Health South Florida, highlighted underestimated toxicities, including infectious complications. Despite prophylactic measures, unexpected viral reactivations pose challenges. Lowering toxicities remains elusive, with the potential for increased cytokine release syndrome with combination therapies.

In an interview with Targeted Oncology^TM, Koehne provided a comprehensive overview of the dynamic landscape and evolving strategies in immunotherapy for hematologic malignancies.

Targeted Oncology: What are the big shifts happening in immunotherapies development in hematologic malignancies?

Koehne: There is certainly a big shift in treating hematologic malignancies at the current time, with a focus on immunotherapies. They're rapidly developing to treat multiple myeloma, leukemia, [and] lymphoma. There are 3 different categories of immunotherapies that I would like to highlight a little bit.

Number 1, they are well established and well known, CAR T cells. Then, we should not forget there is a rapid development in bispecific antibody treatments right now. Thirdly, we have antibody-drug conjugates. Now, what is the difference between these 3 treatment approaches?

Again, the CAR T cells have to be established from the patient that undergoes the treatment after gene modification of the patient's own T cells with a construct that leads to specific expression of a marker that allows targeting the T cell to the malignant cell. Now that is a labor-intensive process and needs to be individualized. In contrast, that is why the bispecific antibodies may play a significant role right now. The bispecific antibodies are available immediately. They are an off-the-shelf product that allows patients with similar markers to get a T cell to the tumor cell, which then allows us to have the endogenous T cells, which are patient's own T cells, home to the tumor site, and have a similar effect to the CAR T cells. The third is the antibody-drug conjugates, which is an antibody targeting the tumor cell. It has at the tail end, a toxin that gets by binding to the tumor cell [and] will then get integrated and leads to the cell death of the tumor cells. Those are the 3 variants that we are exploring right now.

There is a rapid development in finding additional diagnoses and criteria to use these immunotherapies. The challenges we have are, number 1, we do not really know whether the 1 is better than the other,and number 2, there is a rapid development to move away from monotherapy to combination therapies. That is of significance because we don't know whether or not 2 at the same time, simultaneously or in sequence, induce an improved effect than 1 alone.I would suspect it might be, but we don't know whether or not that also leads to increased toxicities. 

Are there any ways to lower toxicities with these agents?

We are not there yet [with] lower toxicities. Based on my experience and based on my observations by treating patients now with immunotherapies, weunderestimated the toxicities that are associated with these treatments. They are effective, no question about it,but I think we underestimated the toxicities. We talked a lot about cytokine release syndrome, which is associated with the CAR T cells and the bispecific antibodies. We talked a lot about neurotoxicity or [immune effector cell-associated neurotoxicity syndrome] that is associated with the CAR T cells or bispecific antibodies.

But now, it is becoming increasingly clear that, at least from my perspective, we have not expected the infectious complications that are associated with the CAR T cells, bispecific antibodies and the antibody conjugates because they are similar. Viral reactivations, for example, are similar to what we observed in allogeneic stem cell transplant recipients. I suspect that we did not expect that form of toxicity with these combinations. In our center, we have prophylaxis for all the patients that undergo CAR T cells or bispecific antibodies with antiviral drugs and antibiotics, similarly to what we do for patients with allogeneic stem cell transplants. Despite this, we do see some significant viral reactivations that we absolutely have not expected to occur in patients after CAR T-cell therapies.

As a consequence of these treatments, sometimes there are other complications that we have to keep an eye on.The question is, is there a development in sight that would lead to lower toxicities following these immunotherapies? My answer is not yet.

We can potentially expect that cytokine release syndrome and toxicities may be even higher if you give 2 drugs at the same time. While we do not know that yet, it may also be that in combination, we may be able to reduce toxicities.

What are you most excited about in the field of immunotherapy for hematologic malignancies?

Over the last 2 years alone, the FDA approved for new drugs to bispecific antibodies and 2 new CAR T-cell approaches for multiple myeloma. Now, those treatment options, particularly for multiple myeloma, were extremely limited. We now have an unbelievable armamentarium to treat patients with multiple myeloma and lymphoma as it is, which we did not have before. That was exciting.

In other words, now before we must call it quits to treat a patient, we now have additional options. We can, therefore, maintain the patient with a good quality of life and prolong the life significantly. With that, particularly multiple myeloma turns more into a chronic disease than an acute malignancy that will likely lead to the end of the life of the patient anytime soon.

Now, that is certainly exciting from my perspective for all the hematologic malignancies. But what we really need to understand is, how can we best optimize the sequence of these treatments? If a physician is not a transplant physician, they will always say, “Let's get rid of transplantation.” But the fact is that it is not happening anytime soon. Autologous transplants are so well tolerated. The morbidity after autologous transplant is less than 1%. So why should we get rid of the most effective treatment that we have and replace it with others, rather than to leave it where it is and have the others follow up? Autologous transplantation is effective, and the [adverse] effects are a lot less than bispecific antibodies and CAR T cells.

Now with the testing of minimal residual disease [MRD], we have an early detection of recurrence of the disease. The drive in the hematologic malignancies is to get the patient's minimal residual disease negative and you do not want to do that with strong chemotherapy. You can do this with immunotherapy and maintain the patient's minimal residual disease negative. There are a lot of clinical trials with virus-specific antibodies right now that allow us to use bispecific antibodies. The minute the patients become MRD-positive again after autologous stem cell transplantation, [it is possible] to catch the recurrence of disease. That also, I think, is true for acute myeloid leukemia, lymphoma, and multiple myeloma. It's also an exciting path and the nice tool that we have right now to improve progression-free survival whilemaintaining quality-of-life of the patient.