The Next Frontier of CAR-T Therapies: Off-the-Shelf Therapies

Just over a year and a half ago, the U.S. FDA approved the first two CAR-T cell therapies: Novartis’ Kymriah for acute lymphoblastic leukemia (ALL) and Gilead-owned Kite Pharmaceutical’s Yescarta for certain types of large B-cell lymphomas, a type of non-Hodgkin lymphoma.

Those are both autologous therapies, meaning they are patient-specific. The patient’s own T-cells (a subtype of white blood cell) are collected from their blood, preserved and shipped to a manufacturer, genetically engineered to recognize and attack the patient’s cancer cells by modifying the T-cell’s receptors (now called chimeric antigen receptor T-cells, or CAR-T cells), then reintroduced into the patient via infusion.

While this type of personalized therapy is revolutionizing cancer treatment and healthcare, it has some formidable limitations.

Limitations with current autologous CAR-T therapies

Because it’s patient-specific, each treatment can only be used for that one patient; if patient B received patient A’s treatment, then patient A’s CAR-T cells would attack all of patient B’s cells (not just their cancer cells), recognizing them as ‘foreign’.

This patient-specific nature also means labor-intensive work and increased treatment production time – usually taking 3 to 4 weeks to manufacture – while running against the ticking cancer clock. Although a few weeks doesn’t sound like that long when you consider the work that goes into creating a personalized therapy, it is longer than many non-personalized treatments, which are available to the patient almost immediately.

The labor-intensive work to personalize the T-cells also heavily drives up the treatments’ price tags - $475,000 for Kymriah and $373,000 for Yescarta.

To resolve these issues, research is now pushing towards the next generation of CAR-T therapies – allogenic, or “off-the-shelf” treatments that can be mass manufactured from a healthy donor’s cells and used for multiple patients.

Off-the-shelf CAR-T therapy research

Researchers at University of California, Los Angeles (UCLA) were able to turn pluripotent stem cells (which can be changed into almost any cell type) into T-cells through structures called artificial thymic organoids. These organoids (miniature, simplified versions of three-dimensional organs derived from stem cells) mimic the thymus, the organ where T-cells are made from blood stem cells in the body.

In their study published in Cell Stem Cell in January, they demonstrated that the three-dimensional environment of artificial thymic organoids allows for successful T-cell maturation. Importantly, they created mature T-cells from both kinds of pluripotent stem cells used in research: human embryonic stem cells (from donated preimplantation human embryos) and induced pluripotent stem cells, called iPSCs (which are reprogrammed from healthy adult donor tissue, such as skin or blood cells).

“What’s exciting is the fact that we start with pluripotent stem cells,” Gay Crooks, the study’s senior author and director of the Cancer and Stem Cell Biology Program at the UCLA Jonsson Comprehensive Cancer Center, said in a press release. “My hope for the future of this technique is that we can combine it with the use of gene editing tools to create ‘off-the-shelf’ T-cell therapies that are more readily available for patients.”

The researchers showed that they could create T-cells that can target and kill tumors in mice by genetically engineering the pluripotent stem cells to express a specific cancer-targeting T-cell receptor.

“Once we create genetically edited pluripotent stem cell lines that can produce tumor-specific T-cells in artificial thymic organoids, we can expand those stem cell lines indefinitely,” said the study’s co-first author and Crooks’ lab associate project scientist Amelie Montel-Hagen.

As promising as this technology is, there are still some kinks to work out. Artificial thymic organoid-created T-cells still express surface molecules that would not match every patient, causing the patient to reject the T-cells.

“Our next step will be to create T-cells that have the receptors to fight cancer but do not have the molecules that cause the rejection of the cells, which would be a major step toward the development of universal T-cell therapies,” said Christopher Seet, the study’s other co-first author and a clinical instructor in the division of hematology-oncology at UCLA.

Their artificial thymic organoid technology was licensed to Gilead’s Kite Pharma back in July 2016. In April 2017, they first published their technology in Nature Methods, demonstrating that artificial thymic organoids allowed for T-cell maturation from adult blood stem cells. Kite has not released any further updates on their use of the organoid technology.

Off-the-shelf CAR-T therapies in biopharma

Off-the-shelf therapy is also a hot topic in biotechs now, with multiple companies working towards the next breakthrough therapy, including UCLA/Kite’s artificial thymic organoid technology.

Cellectis is a pioneer in gene editing (using TALEN technology) and allogeneic CAR-T therapy, also called Universal CAR-T cells (UCARTs). They have a range of UCARTs under development. UCART123, which targets CD123⁺ leukemic cells in acute myeloid leukemia (AML), is being studied in two currently recruiting open-label Phase 1 trials: AML123 studying the therapy’s safety and efficacy in an estimated 156 AML patients, and ABC123 studying the therapy’s safety and activity in an estimated 72 patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). UCART22 is designed to treat both CD22⁺ B-cell acute lymphoblastic leukemia (B-ALL) and CD22⁺ B-cell non-Hodgkin lymphoma (NHL). Cellectis reported that UCART22 is in an open-label, dose-escalating Phase 1 trial to study its safety and activity in relapsed or refractory CD22⁺ B-ALL patients. UCARTCS1 is being developed to treat CS1-expressing hematologic malignancies, such as multiple myeloma (MM). UCARTCLL1 is in preclinical development for treating CLL1-expressing hematologic malignancies, such as AML.

Cellectis is also jointly developing allogeneic CAR-T therapies with Allogene Therapeutics, another allogeneic CAR-T-focused biotech. ALLO-501 targets CD19 and is being developed to treat relapsed or refractory NHL. The FDA granted investigational new drug (IND) status to ALLO-501 in January and a Phase 1 trial is expected to begin within the next few months. Two therapies are exclusively licensed to Allogene: ALLO-715, which targets B-cell maturation antigen (BCMA), for treating relapsed or refractory MM; and ALLO-819, which targets CD135 (also called FLT3), for treating relapsed or refractory AML.

Allogene, in collaboration with Cellectis and Pfizer, have three active open-label, single-arm Phase 1 trials for an off-the-shelf allogeneic CAR-T therapy called UCART19 in patients with relapsed or refractory CD19⁺ B-ALL: PALL, which is studying the therapy’s safety and feasibility in 18 pediatric patients; CALM, which is a dose-escalating study evaluating the therapy’s safety and tolerability in 40 adult patients; and a long-term safety and efficacy follow-up study in 200 patients with advanced lymphoid malignancies.

Allogene reported some proof-of-concept results at the American Society of Hematology (ASH) meeting back in Dec 2018. Data from the first 21 patients from both the PALL (n=7) and CALM (n=14) Phase 1 studies were pooled. Of the 17 patients who received UCART19, fludarabine/cyclophosphamide (a standard chemotherapy drug combination that causes lymphodepletion, or destruction of lymphocytes and T-cells), and an anti-CD52 monoclonal antibody, 14 patients (82 percent) achieved complete remission with significant UCART19 cell expansion. In stark contrast, the four patients who only received UCART19 and fludarabine/cyclophosphamide (no anti-CD52 antibody) saw no response and minimal UCART19 expansion. This highlights the apparent importance of an anti-CD52 antibody for the efficacy of allogeneic CAR-T therapies. The safety data also looked relatively promising: no cases of grade 3 or 4 neurotoxicity, only 2 cases of grade 1 graft-versus-host disease (10 percent) and none any higher, 3 cases of grade 3 or 4 cytokine release syndrome that were “generally manageable” (14 percent), 5 cases of grade 3 or 4 viral infections (24 percent), and 6 cases of grade 4 prolonged cytopenia (29 percent).

Although this young allogeneic CAR-T technology is still being developed, sights are already set on what the manufacturing efficiency would be and how it would compare to autologous CAR-T therapy production. For example, Allogene states a potential to treat 100 patients per batch of allogeneic CAR-T cells.