Allogeneic versus patient-derived CAR T therapies in multiple myeloma

An overview of patient-derived versus allogeneic CAR T products by the Multiple Myeloma (MM) Hub, prompted by the recent FDA approval of the MUNDI-01 trial using the off-the-shelf CAR T product, UCARTCS1.¹ The MM Hub were also pleased to speak to Steering Committee member, Maria-Victoria Mateos, on the topic of allogeneic versus patient derived CAR T therapy. Professor Mateos's expert opinion can be found at the end of this article.

CAR T-cell therapy is a novel treatment whereby T-cells are removed, genetically engineered to express a specific CAR construct, expanded ex vivo, and then infused into a patient.² While autologous CAR T-cells have been successfully used in patients with aggressive lymphomas or leukemias to induce long-lasting responses, their efficacy in patients with MM is short lived. Various strategies are currently pursued to optimize CAR T-cell therapy for the treatment of MM.³

It was announced earlier this month (2 April 2019) that the first allogeneic CAR T product for MM – UCARTCS1 – has been approved for phase I trials by the US Food and Drug Administration (FDA). In light of this, the MM Hub has summarized the potential advantages and limitations of patient-derived CAR T therapy and allogeneic CAR T products; we have also included further information on the UCARTCS1 trial, MUNDI-01.¹

Patient-derived (traditional) CAR T-cell therapy

Currently, there are two FDA approved CD19 CAR T products; tisagenlecleucel and axicabtagene ciloleucel. Both are indicated for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) in adults and tisagenlecleucel is also indicated for use in pediatric patients with B-cell precursor acute lymphoblastic leukemia in second or later relapse.^4,5 These CD19 CAR T-cells are the first commercially approved therapies using gene-transfer. However, due to their known side effects of cytokine release syndrome (CRS) and neurologic events (NEs) they are regulated with Risk Evaluation and Mitigation Strategies to ensure these are appropriately managed.³

Following in the footsteps of these successful developments and authorizations are many more CAR T products currently in pre-clinical development and clinical trials for other hematological malignancies such as MM.

In MM, the B-cell maturation antigen (BCMA) has been identified as a viable target and anti-BCMA CAR T products have had preliminary success in phase I trials.^2,6 To understand the status of CAR T in MM and to see the latest clinical data, please click here. To read more about when to use CAR T MM, please click here.

Naturally, there are some issues to overcome with patient-derived CAR T therapy, which are discussed, along with the positive attributes, in Tables 1 and 2 below.

Allogeneic CAR T-cell therapy

The cells used in allogeneic CAR T therapy may come from a variety of sources, which include:²

1. Manufacturing cells from prior hematopoietic stem cell transplant (HSCT) donor which would be human leukocyte antigen (HLA)-matched
2. Using third-party viral specific T-cell donors (partial HLA-match)
3. Using healthy donor cells that have had their genes edited
4. Using non-gene edited CAR T-cells that are mismatched
5. Making donor T-cells resistant to lymphodepleting agents
6. Using induced pluripotent stem CAR T-cells

Producing allogeneic CAR T-cells from the peripheral blood mononuclear cells of healthy donors who are not HLA-matched to the patient is one of the methods furthest in development. The healthy donor cells are transduced with a CAR, as with traditional CAR T therapy, but the end product is not HLA-matched to the donor.² The advantages and limitations of allogeneic CAR T products derived from healthy donors are discussed in Tables 3 and 4.

Potential advantages and limitations of patient-derived versus allogeneic CAR T

In the tables below, the MM Hub has summarized some of the potential advantages and limitations to both patient-derived CAR T therapy and allogeneic CAR T products.

Table 1: advantages and limitations of manufacturing patient-derived CAR T products^{2, 3, 7–9}

Table 2: advantages and limitations in the clinical use of patient-derived CAR T products^{2, 3, 7–9}

Table 3: advantages and limitations of manufacturing allogeneic CAR T products from healthy donors^{2, 3, 7–9}

Table 4: advantages and limitations in the clinical use of allogeneic CAR T products derived from healthy donors^{2, 3, 7–9}

Case study: off-the-shelf allogeneic CAR-T product UCARTCS1¹

UCARTCS1 is an off-the-shelf allogeneic CAR T product generated from healthy donor cells. An investigational new drug (IND) application for a phase I trial in patients with MM was filed in December 2018 and approved in January 2019.

The MUNDI-01 trial will investigate the safety, expansion, persistence and clinical activity of UCARTCS1 in a dose-escalation and dose-expansion study. The first, second and third doses will be 1 x 10⁶ cells/kg, 3 x 10⁶ cells/kg and 9 x 10⁶ cells/kg respectively. The dose-limiting toxicity period is 28 days in line with a 28-day staggering for the first 2 patients at each dose level.

The trial is currently expected to be run by Dr. Krina Patel at the MD Anderson Cancer Center in Houston, TX, with two additional sites enrolling in the United States.

About UCARTCS1¹⁰

• The target of UCARTCS1 is CS1 (SLAMF7) which is highly expressed on MM cells
• Product is derived from peripheral blood mononuclear cells of normal healthy donors
• The CAR T product is created using TALEN® gene editing technology⁷
  • The TCRα constant (TRAC) and SLAMF7 genes are inactivated
• In vitro and in vitro studies have shown that UCARTCS1 cells target and lyse primary MM tumor cells. In these studies, in response to primary MM tumor cells, the UCARTCS1 cells:
  • Specifically degranulated
  • Produced T_h1 and T_c1 cytokines
  • Proliferated