GENE THERAPY

John Tisdale, chief of the Cellular and Molecular Therapeutics Branch at the National Institutes of Health said that allogeneic hematopoietic stem cell transplantation (HSCT) can cure sickle cell disease by replacing the patient’s stem cells with another person’s stem cells. However, an emerging approach is to edit the patient’s cells in order to correct the genetic mutation. Sickle cell disease is a devastating disease that affects every organ in the body and results in anemia, pain, morbidity, and early mortality, he said. The disease occurs because of a single substitution at position 6 of the ß-globin chain, which causes abnormal red blood cells. It is a rare disease in the United States, affecting about 100,000 people, but it affects millions in sub-Saharan Africa (Piel et al., 2017). Tisdale said that there are only a handful of therapies for sickle cell disease, and they are largely supportive rather than curative. Bone marrow transplantation is the one proven approach for curing sickle cell disease. A retrospective study found that event-free and overall survival rates were quite good in transplant recipients, particularly for those who were children at the time of transplant, and those who received an human leukocyte antigens (HLA)–matched sibling graft (Eapen et al., 2019).

By studying patients who have undergone HSCT for sickle cell disease, Tisdale and his colleagues sought to understand the level of donor cells that are necessary for reversal of the disease (Fitzhugh et al., 2017). Several patients had robust engraftment following the transplant, but then experienced declining levels of donor cells; Tisdale and his colleagues determined that a patient needs 20 percent normal cells in order to be cured, and that these levels are affected by differences between the survival time of donor and recipient red blood cells. Given these results, Tisdale asked, is it possible to achieve the 20 percent level with gene therapy of the patient’s own cells? Research on this approach has been conducted in animal models and is now in phase I/II clinical trials, said Tisdale. The gene therapy approach involves making viral vectors with a copy of the corrected gene, and using this vector to move the genetic material into the hematopoietic stem cell. If successful, it results in normal hemoglobin production from the cells that were infused.

In recent years, gene therapy has “come of age,” said Tisdale, and these advances have moved gene therapy for sickle cell disease closer to reality (Dunbar et al., 2018) (Figure 5-1). The first success in this area was using lentiviral vectors that were based on human immunodeficiency virus (HIV); in trials involving nonhuman primates, this approach resulted in the necessary levels of normal blood cells. Once this was achieved, said Tisdale, a clinical trial was launched to test the approach in humans. Researchers refined parts of the approach, including optimizing precollection transfusion and the hematopoietic stem cell source. Results of this trial found that 30 months after LentiGlobin transfusion, about half of patients’ hemoglobin was coming from the vector, and they had a normal total hemoglobin level (Kanter et al., 2022). Importantly, said Tisdale, severe vaso-occlusive episodes (acute pain that requires care at a medical facility) disappeared completely after 6 months. Similarly, patients who received standard HSCT treatment for sickle cell disease also experienced a dramatic reduction in vaso-occlusive events within the first year after the transplant.

Figure 5-1

Historical overview of hematopoietic stem cell transplantation gene therapy. NOTE: CRISPR/Cas9: clustered regularly interspaced short palindromic repeat (CRISPR)–CRISPR-associated 9 (Cas9) nucleases; HSC: hematopoietic stem cell; HSCT: hematopoietic (more...)

We know that allogenic transplantation works for curing sickle cell disease, said Tisdale; risk of stroke, pain, acute chest syndrome, and other symptoms are drastically reduced. Gene therapy is demonstrating efficacy in sickle cell disease and other diseases, and “we are hopeful” that the improvements seen in allogenic transplants will also be seen with the gene therapy approach. However, there is a need for long-term studies, both of allogenic transplant recipients and of autologous gene therapy transplant recipients, in order to better understand the effect and long-term outcomes for both approaches. Unfortunately, much of the accumulated organ damage in sickle cell patients persists even after the disease itself is cured; Tisdale said that application of curative approaches earlier in the course of the disease would likely improve outcomes.

CAR T-CELL THERAPY

Chimeric antigen receptor (CAR) T-cell therapies have the potential to revolutionize cancer care and have a significant positive effect on disabilities, said David Porter, the director of Cell Therapy and Transplant at the University of Pennsylvania. Many cancer cells have well-characterized surface proteins, and these proteins can be targeted to kill the cell with various modalities, including monoclonal antibodies, engineered antibodies, and immune T cells. One specific protein that is an ideal target is CD19, which is expressed on nearly all B-cell malignancies. CD19 is targeted with chimeric antigen receptor modified T cells. These cells consist of different parts, explained Porter: an antibody to target the specific protein on the cancer cell, sequences to bring and stabilize the protein on the surface of the T cell, and signals for T-cell activation, growth, and survival. Similar to gene therapy, lentivirals are used to bring new coding into the T cell. The gene gets integrated, then directs expression of a new protein that gets transported and integrated into the cell surface. The CAR modified T cell can then recognize and kill CD19+ cells.

CAR T-cell therapy works, and when it works, “it can work dramatically,” said Porter. It has been tested in most B-cell malignancies, and in patients who had very little probability of remission or cure (Table 5-1). For example, in patients with relapsed, refractory acute lymphocytic leukemia (ALL), 80 to 90 percent achieve complete remission and 50 to 60 percent are leukemia free 6 to 12 months later. In other diseases—non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL), and multiple myeloma (MM)—anywhere between 50 to 100 percent of patients respond to the therapy and 30 to 70 percent have long-term improvement.

TABLE 5-1

CAR T Cells for B-Cell Malignancies.

Porter explained the process of CAR T-cell therapy. First, a patient undergoes leukophoresis to collect T cells; these cells are exposed to a virus with new genetic material. The virus infects the cells, bringing in the new gene, and cells are grown in the laboratory for 1 or 2 weeks. Once there are a sufficient number of T cells, the genetically modified T cells are isolated. The patient undergoes chemotherapy that is designed to weaken their immune system to improve acceptance of the new T cells and then receives the genetically modified T cells. In many circumstances, this process can be conducted on an outpatient basis, said Porter.

One of the first applications of CAR T-cell therapy was for patients with relapsed or refractory ALL, a condition with a median survival rate of less than 1 year and a 3-year survival rate of less than 25 percent. Allogeneic transplant has been used with success in patients with relapsed ALL, but for patients with refractory ALL, it is largely ineffective, Porter said. Patients with relapsed or refractory ALL were given CAR T-cell therapy as part of a clinical trial (Maude et al., 2018); participants were children and young adults who were likely to die of their disease within a few weeks without effective therapy. Of the 75 patients treated, 81 percent achieved complete remission, and survival was around 50 percent at 1 year. The majority of relapses occurred by 1 year, and patients were unlikely to relapse after that time. This trial, said Porter, led to U.S. Food and Drug Administration (FDA) approval of this application of the CAR T-cell approach. There are now five FDA-approved CAR T-cell products for five different indications, all in B-cell malignancies.

Like most therapies, CAR T-cell therapy comes with some toxicities and side effects, said Porter. The major unique toxicity of CAR T cells is cytokine release syndrome, in which inflammatory molecules are released because of immune cell activation. Although severe, the syndrome can be managed quite effectively in most patients with the use of an antibody called tocilizumab, he said. Another unique toxicity is an unusual neurologic side effect that causes patients to have difficulty speaking, become confused, have seizures, and even become comatose. This toxicity can be managed with the administration of steroids. The “remarkable thing,” said Porter, is that nearly all patients recover from their toxicities by day 30. Treatment-related mortality is in the low single-digit range. One longer-term toxicity, however, is hypogammaglobulinemia (poor antibody production), which can bring increased risk of infection; this toxicity can be managed with intravenous immunoglobulin infusions when appropriate.

Many patients treated with CAR T-cell therapy achieve complete remission and are “alive and well” many years after therapy, which is a dramatic improvement compared to other available therapies. Despite these results, “people tend to be very careful” and say CAR T cells “may” be curing patients. Porter said that with these results, “it is time that we can say” that CAR T cells are indeed curing patients who previously had incurable, rapidly progressing, life-threatening malignancies.

PREVENTING AND MITIGATING HSCT COMPLICATIONS

Steven Devine, chief medical officer at the National Marrow Donor Program (NMDP) and associate scientific director at the Center for International Blood and Marrow Transplant Research (CIBMTR), said that in addition to the development of alternatives to HSCT such as gene therapy and CAR-T cell therapy, there are also efforts to improve HSCT itself by preventing or reducing complications and disability. Among these efforts are the development of approaches to prevent GVHD, particularly in patients without HLA-matched donors. If the complications caused by mismatched-HLA donors can be reduced, said Devine, access to transplantation can be improved and researchers can focus attention on preventing relapse.

To be widely applicable and represent progress, said Devine, approaches to prevention of GVHD must meet four criteria. First, they must increase access to transplant by mitigating the effect of HLA mismatch. Second, they must be less toxic than current approaches and not contribute to late toxicity. Third, new approaches should have less effect on immune reconstitution. Finally, new approaches should focus on identifying those at greatest risk of developing GVHD rather than taking a one-size-fits-all approach, said Devine. There are two general approaches for preventing GVHD: pharmacological and physical manipulation of the graft (e.g., T cell depletion). Devine said that currently two drugs represent real advances in the prevention of GVHD.

Posttransplant cyclophosphamide (PTCy) has shown promise in trials comparing it to cyclosporine-based GVHD prophylaxis. One randomized trial (De Jong et al., 2019) found that patients treated with PTCy had a better rate of GVHD- and relapse-free survival. Following on this evidence, the PROGRESS II trial (Luznik et al., 2022) compared three groups: patients who received a bone marrow graft with immune suppression (tacrolimus/methotrexate), those who received PTCy after bone marrow graft, and those who received a CD34-selected peripheral blood stem cell graft. Devine said that there were no differences in the primary endpoint of chronic GVHD-free, relapse-free survival. There was less GVHD in the T cell depletion arm, but a higher risk of treatment-related mortality owing to a higher rate of infections. The PTCy arm, which did not include calcineurin inhibitors, had similar results to the patients who received immune suppression, which suggests that this could be an alternative approach for patients who enter the transplant process with renal toxicity. The PROGRESS III trial (https://clinicaltrials.gov/ct2/show/NCT03959241) is again examining GVHD-free and relapse-free survival, comparing the treatment of tacrolimus and methotrexate to a treatment of PTCy combined with tacrolimus and mycophenolate mofetil; results are expected shortly.

While the data on the use of PTCy are still accruing, said Devine, transplant centers have already “jumped onboard.” Data collected by CIBMTR from U.S. transplant centers show that the use of PTCy increased substantially in all transplant groups between 2016 and 2020 (Table 5-2). More recent data suggest that about 35 to 40 percent of recipients of matched unrelated donor transplants now receive PTCy, said Devine.

TABLE 5-2

Increase in Use of Posttransplant Cyclophosphamide in Patients Receiving Hematopoietic Stem Cell Transplants.

Compared to HLA-matched sibling transplants and HLA-matched unrelated donor transplants, patients who receive mismatched transplants have worse rates of overall survival, said Devine. Further, each mismatch in HLA is associated with about a 10 percent decrease in survival (Lee et al., 2007).

Currently, patients that are African American are far less likely to find an 8/8 HLA match (around 20 percent), compared to White patients (around 75 percent) (Figure 5-2). If transplants could be conducted successfully with 7/8 donors, this would increase donor availability for patients who are African American to 72 percent, and if 6/8 donors were added, it would increase availability to 97 percent. Given this potential, the NMDP sought to evaluate PTCy in HSCT patients with a mismatched or unrelated donor (Shaw et al., 2021). The study enrolled 80 patients without a well-matched donor and provided PTCy after bone marrow graft. It is notable, said Devine, that 48 percent of enrolled patients in this trial were racial or ethnic minorities, compared to about 10 percent in most transplant clinical trials. The results were positive: 1-year overall survival rate was 76 percent, and there were no obvious differences between the mismatched unrelated donor transplant patients and recipients of haplo-identical related transplants. This suggests, said Devine, that mismatched unrelated donor transplantation using PTCy offers a transplant option for patients who do not have a suitable alternative donor. The NMDP recently began a follow-on study that will examine the use of PTCy in transplantations involving mobilized peripheral blood, rather than only bone marrow transplants. The trial includes a pediatric and young adult stratum, in addition to two adult strata, said Devine.

Figure 5-2

Disparities in HLA match rates by race: HLA match rates for five broad race groups (as of November 15, 2021). NOTES: HLA = human leukocyte antigens; AFA = African American; API = Asian Pacific; CAU = Caucasian; HIS = Hispanic/Latino; NAM = Native American. (more...)

Another drug with the potential to prevent GVHD, said Devine, is abatacept, which is currently approved for rheumatoid arthritis in the GVHD setting. Emerging data suggest that outcomes for patients who received abatacept in 7/8 matched transplants are similar to outcomes for patients with 8/8 matched transplants and perhaps were better than standard-of-care (Watkins et al., 2021). On the basis of these results, the FDA has granted priority review for abatacept to prevent moderate to severe acute GVHD in HSCT patients, said Devine.¹

Graft manipulation is another strategy for preventing GVHD. While T cell depletion is an established approach, said Devine, there are now better tools to manipulate and select cells. Bulk T-cell depletion is effective at preventing acute and chronic GVHD, but it is associated with prolonged immune reconstitution and infectious complications. There are trials currently under way to evaluate how graft manipulation can be employed in order to mitigate GVHD while retaining the intended effect of the graft (e.g., graft-vs.-leukemia effect).

There are encouraging data emerging for both pharmacological and physical approaches to preventing GVHD, said Devine. These innovative approaches may greatly improve access to transplantation, particularly for racial groups whose access is currently limited. Improvements in access will increase opportunities for patients with serious nonmalignant disorders, he said, and will allow researchers the opportunity to focus on other aspects of transplantation, such as preventing relapse.

DISCUSSION

Following the presentations, Thompson led a discussion among the panelists by asking questions posed by workshop participants.

Q1: How do these alternative therapies compare to HSCT in terms of long-term or late effects? Are there any potential additional late effects from these new therapies?

One of the major differences between the newer therapies and the conventional allogeneic transplant, said Tisdale, is that using your own cells mitigates the risk of developing serious conditions such as GVHD. However, there is some evidence that autologous gene therapy may be associated with the risk of late malignancies. While this is also a risk in the allogeneic transplant setting, it is unknown whether the frequency is higher or lower. Porter added CAR T-cell therapy has several benefits over HSCT, including mitigated risk of GVHD, no high doses of chemotherapy, and better chance for full recovery. The most prominent concern with CAR T-cell therapy is the risk of hypogammaglobulinemia, which leaves patients without the ability to make antibodies and respond to vaccines. This is particularly relevant in the COVID-19 era, he said.

Q2: To what extent can these emerging therapies address current disparities in both access and outcomes? What potential is there for exacerbating disparities?

In general, said Tisdale, the accessibility gap widens as treatments become more complicated and more expensive. As new approaches are developed, it is critical that attention is paid to rolling them out in ways that address rather than worsen disparities. The use of CAR T cells, said Porter, has the potential to address disparities; because they are autologous, they can be made available to anyone regardless of their background. However, in practice, historically disadvantaged populations are still often unable to access new therapies because of issues with appropriate referrals, lack of access to major medical centers, and the cost of the therapies. Devine said that “the technology is here to overcome the HLA barrier to transplantation,” but the financial, social, cultural, and educational barriers persist. Further, said Thompson, preexisting disparities and social determinants of health can perpetuate and exacerbate disparities. For example, while gene therapy can be used to cure sickle cell anemia, patients with existing organ damage will likely still have a degree of disability. Therefore, patients who are able to access treatment earlier—likely those with more resources and connections—will have better outcomes.

Q3: After a curative treatment—whether gene therapy, CAR T cells, or HSCT—how easy is it to predict an individual patient’s needs and potential complications?

From the Social Security Administration's perspective, said Thompson, it may be the case that a person’s needs posttherapy will not always be easy to predict; she asked panelists to comment on this. Tisdale responded that for sickle cell disease, outcomes depend largely on age and accumulated organ damage: “We are at best left where the patient was when they came to cure.” For example, he said, a patient who is in renal failure or on dialysis before treatment will continue to need dialysis after. Likewise, a patient who is disabled by chronic pain caused by bone infarcts will continue to be disabled even after the underlying disease is cured. Tisdale noted that some organs do improve after curative therapies, including heart, liver, and lungs. However, in general, the younger and less disabled the patient is when treatment begins, the better the outcomes.

Porter agreed that in general, curative treatments do not cure prior damage. Some of the diseases that can be treated with CAR T cells and HSCT are traditionally treated with multiple long-term rounds of intensive chemotherapy that result in cumulative damage. Given the fact that emerging treatments have the potential to cure the disease before the patient is exposed to long-term toxicity, he said, perhaps “we should be thinking about applying these therapies sooner.” If a patient with lymphoma relapses after first-line chemotherapy, CAR T-cell therapy might be a better option than subjecting them to more chemotherapy.

Q4: What types of studies and data are necessary in order to assess the long-term outcomes, including disabilities, for both HSCT and emerging therapies?

There is a need for more long-term follow-up studies that look at the out-comes that patients, families, and providers care about, said Tisdale. These data are essential for providers to do a better job of caring for patients in the years after treatment, and for many applications of HSCT the data simply do not exist. Porter said that the CIBMTR collects thousands of data points on long-term outcomes for HSCT, and that “as a community, it’s incumbent on us to provide that data.” He argued that there is, in fact, a fair amount of data available about long-term outcomes related to HSCT, but that it is poorly disseminated. There is a need to do a better job of educating patients, providers, and primary physicians about these outcomes and long-term disabilities, he said. Thompson agreed with this point and said that many long-term HSCT survivors may no longer be treated at transplant centers but instead are in community practices with physicians who are unfamiliar with the needs of transplant patients. The fields of gene therapy and CAR T cells are in their infancy, said Porter, so there is a lack of long-term outcomes data. More than 1,000 different cell therapies are currently in development, and the field is set to “explode.” Now is the time, he emphasized, to set up a mechanism to collect long-term data in this area.

CLOSING REMARKS

To conclude the workshop, Rosenbaum thanked the speakers, the workshop participants, the planning committee, the staff, and the Social Security Administration for their part in putting together this “rich discussion.” The workshop presentations and discussions, she said, offered an incredible amount of insight into the promises and challenges of hematopoietic stem cell transplantation therapy and what is on the horizon. After these remarks, Rosenbaum adjourned the workshop.