CAR T-Cell Therapy Surpasses 90% Complete Remission Rate in Pediatric ALL

The chimeric antigen receptor (CAR) T-cell therapy JCAR017 elicited a 91% complete remission rate in pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL), according to results from a phase I trial presented at the 2015 AACR Annual Meeting.

In the treated patients, complete remissions were observed in 20 of 22 patients, as ascertained by flow cytometry.  Complete remissions were observed with all applied doses of JCAR017 and in patients who had been treated already with CD19-targeted therapies.  Severe neurotoxicity and/or severe “cytokine release syndrome” was observed in 8 patients. In total, 4 patients have relapsed—only one of which had CD19-positive disease.

“The 91% remission rate in this phase I study of JCAR017 is highly encouraging, particularly when considering these pediatric patients failed to respond to standard treatments,” Michael Jensen, MD, said in a statement. “Based on these results we are eager to advance this study, and to continue advancing the use of cell therapies to change how we treat cancer and provide patients the opportunity for better treatment options.”

Jensen serves as the director of the Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, and is also the scientific co-founder of Juno Therapeutics, which is the company that is developing JCAR017.  JCAR017 is being evaluated in an ongoing phase I/II study for pediatric and young adult patients with relapsed/refractory CD19-positive leukemia at the Seattle Children’s Hospital.

This  study intends to enroll 80 patients.  The phase I portion enrolled patients who had undergone an allogeneic hematopoietic cell transplant, but the second phase of the study is open to patients, regardless of prior transplant status (NCT02028455).

“Given the impressive clinical results with this defined cell product candidate, we are encouraged to begin testing of JCAR017 in adult patients with B cell malignancies, including non-Hodgkin lymphoma, later this year,” Hans Bishop, chief executive officer of Juno Therapeutics, said in a statement.

Juno also has three other CAR and T cell receptor therapies that are under evaluation in clinical trials.  The furthest along is JCAR015, which received a breakthrough therapy designation from the FDA as a treatment for patients with relapsed or refractory B-cell ALL in November 2014.  In one trial, JCAR015 is being used to treat precursor B cell ALL, which is the condition for which JCAR015 was awarded its orphan drug designation (NCT01840566).  In a second trial, patients with relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL) are being treated with high dose therapy and autologous stem cell transplantation followed by infusion of JCAR015 (NCT01044069).

There are plans for future clinical trials to explore Juno’s CAR T cell therapies in combination with immune checkpoint inhibitors. Recently, Juno and MedImmune, the biologics research and development arm of AstraZeneca, announced an agreement focused on the clinical development of combination strategies.  A jointly-funded phase Ib study will explore one of Juno’s CD19-directed CAR T cell therapies in combination with the PD-L1 inhibitor MEDI4736 as a treatment for patients with NHL.  It is expected to begin later this year.

“We believe combination strategies such as this will help us better understand the full potential of our engineered T cell platform in both hematological and solid tumor settings,” Mark W. Frohlich, MD, executive vice president, Research & Development, Juno Therapeutics, said in a statement.

MEDI4736 is currently under evaluated in phase III clinical trials that are testing MEDI4736 alone and in combination with the CTLA-4 antibody tremelimumab in patients with a variety of non-small cell lung cancers and in patients with head and neck cancer who have failed prior chemotherapy.

Competition in the field of immuno-oncology has resulted in collaborations between several pharmaceutical companies, outside of the Juno deal. This is evident in the field of CAR-modified T-cell therapy, where collaborations exist between Novartis and the University of Pennsylvania (CTL019) and between Kite Pharma and the NCI (KTE-C19).

In the pediatric oncology space, results from the breakthrough therapy CTL019 were presented at the 2014 ASH Annual Meeting and demonstrated similar findings to those announced for JCAR017. In this phase I trial of 39 pediatric patients with relapsed/refractory ALL, CTL019 demonstrated a 92% complete remission rate. In total, 85% of patients who achieve a complete remission tested MRD-negative by flow cytometry.

Preventing the Rejection of Embryonic Stem Cell Derivatives – Take Two

Yesterday I blogged about the paper from Yang Xu’s group that used genetically engineered embryonic stem cells to make adult cell types that were not rejected by the immune systems of mice with humanized immune systems. I would like to say a bit more about this paper before I leave it be.

First of all, Xu and his colleagues engineered the cells to express the cell-surface protein PD-L1, which stands for programmed cell death ligand 1 (also known as CD274), and another protein called CTLA4-Ig. The combination of these two proteins tends to make these cells invisible to the immune system for all practical intents and purposes.

PD-L1, however, is used by tumor cells to evade detection by the immune system. For example, increased expression of PD-L1 is highly correlated with the aggressiveness of the cancer. One particular experiment examined 196 tumor specimens that had been extracted from patients with renal cell carcinoma (kidney tumors). In these tumor samples, high expression of PD-L1 was positively associated with increased tumor aggressiveness and a those patients that had higher expression of PD-L1 have a 4.5-fold increased risk of death (see Thompson RH, et al., Proc Natl Acad Sci USA 101 (49): 17174–9). In patients with cancer of the ovaries, those tumors with higher PD-L1 expression had a significantly poorer prognosis than those with lower PD-L1 expression. The more PD-L1 these tumors expressed, the fewer tumor-hunting T cells (CD8+ T cells) were present (see Hamanishi J, and others, Proc Natl Acad Sci USA 104 (9): 3360–5).

So the Xu paper proposes that we introduce genetically engineered cells, which are already at risk for mutations in the first place, into the body, that constitutively express PD-L1, a protein known to be highly expressed in the most aggressive and lethal tumors. Does this sound like a good idea?

With respect to CTLA4-Ig, this is a cell-bound version of a drug that has been approved as an anti-transplantation rejection drug called Belatacept (Nulojix), made by Bristol-Myers-Squibb. Since this is a cell-bound version of this protein, it will almost certainly not have the systemic effects of Belatacept, and if the cells manage to release a certain amount of soluble CTLA4-Ig, it is likely to be very little and have no biological effect.

Therefore, this strategy, while interesting, does come with its own share of risks and caveats.

Preventing Rejection of Embryonic Stem Cell-Based Tissues

Embryonic stem cells (ESCs) are derived from human embryos. Because they are pluripotent, or have the capacity to make any adult cell type, ESCs are thought to hold great promise for cell therapy as a source of differentiated cell types.

One main drawback to the use of ESCs in regenerative medicine is the rejection of ESC-derived cells by the immune system of the patient. Transplantation of ESC-derived tissues would require the patient to take powerful anti-rejection drugs, which tend to have a boatload of severe side effects.

However, a paper reports a strategy to circumvent rejection of ESC-derived cells. If these strategies prove workable, then they might clear the way to the use of ESCs in regenerative medicine.

The first paper comes from the journal Cell Stem Cell, by Zhili Rong, and others (Volume 14, Issue 1, 121-130, 2 January 2014). In this paper, Rong and his colleagues from the laboratory of Yang Xu at UC San Diego and their Chinese collaborators used mice whose immune systems had been reconstituted with a functional human immune system. These humanized mice mount a robust immune response against ESCs and any cells derived from ESCs.

In their next few experiments, Xu and others genetically engineered human ESCs to routinely express two proteins called CTLA4-Ig and PD-L1. Now this gets a little complicated, but stay with me. The protein known as CTLA4-Ig monkeys with particular cells of the immune system called T cells, and prevents those T cells from mounting an immune response against the cells that display this protein on their surfaces. The second protein, PD-L1, also targets T cells and when T cells bind to cells that have this protein on their surfaces, they are completely prevented from acting.

CTLA-4 mechanism

Think of it this way: T cells are the “detectives” of the immune system. When they find something fishy in the body (immunologically speaking), they get on their “cell phones” and call in the cavalry. However, when these detectives come upon these cells, their cell phones are inactivated, and their memories are wiped. The detectives wander away and then do not remember that they ever came across these cells.

Further experiments showed that any derivatives of these engineered ESCs, (teratomas, fibroblasts, and heart muscle cells) were completely tolerated by the immune system of these humanized mice.

This is a remarkable paper. However, I have a few questions. Genetic engineering of these cells might be potentially dangerous, depending upon how it was done, where in the genome the introduced genes insert, and how they are expressed. Secondly, if cells experience any mutations during the expansion of these cells, these mutations might cause the cells to be detected by the immune system. Third, do these types of immune repression last long-term? Clearly more work will need to be done, but these questions are potentially addressable.

My final concern is that if this procedure is used widespread, it might lead to the wholesale destruction of human embryos. Human embryos, however, are the youngest, weakest, and most vulnerable among us. What does that say about us if we do not value the weakest among us and dismember them for their cells? Would we allow this with toddlers?

Thus my interest and admiration for this paper is tempered by my concerns for human embryos.