General MM

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 products2, 3, 7–9

Advantages

Limitations

Commercial-scale manufacturing processes have been established

Individual scale production: cell amplification dependent on patient material and lack of standardized product

 

Turnaround time can be 2–3 weeks based on the current processes, during which time disease progression or death may occur.

 

Expensive due to manufacturing costs: may prevent access for many patients

 

If the harvesting or manufacture process fails, the process would either need to be restarted and may no longer be possible

 

Harvesting may not be possible in patients with low lymphocyte counts

 

The product obtained from the patient that is used for manufacturing contains cells in poor health

Table 2: advantages and limitations in the clinical use of patient-derived CAR T products2, 3, 7–9

Advantages

Limitations

Personalized therapy

CRS and NEs associated with CAR T administration

Single-use therapy: the cells are administered once and then expand in the patient compared to regimens of chemotherapy

Lymphodepleting chemotherapy is required to provide an environment for the CAR T-cells to expand. This makes the patients severely immunocompromised.

May be available to patients who are ineligible for HSCT

Currently, most trials are based in the United States (US) and China, with few in Europe and Japan, limiting the availability

Years of clinical experience and data in a group of specific patients

 

Regulatory authorities have already approved the use of some of these CAR T products

 

The side effect profile appears to be predictable and manageable in most cases

 

Table 3: advantages and limitations of manufacturing allogeneic CAR T products from healthy donors2, 3, 7–9

Advantages

Limitations

No risk of production failure as with personalized CAR T

Off-target cleavage: using gene editing technology can cause other, unwanted mutational effects to healthy cells

Less expensive based on large scale production and reduced manufacturing costs which may make these products available to more patients

 

Reduced turnaround time may decrease the proportion of patients who experience disease progression or death before they can receive the therapy

 

Product from these donors is healthy and the end-product is good quality

 

Table 4: advantages and limitations in the clinical use of allogeneic CAR T products derived from healthy donors2, 3, 7–9

Advantages

Limitations

Potential lower risk of graft-versus­-host disease (GvHD) if the endogenous T-cell receptor expression can be disrupted via genome editing (TALEN®) or the major histocompatibility complex (MHC) I is removed. Removing the MHCI complex may prevent natural killer (NK) cells from targeting the CAR T-cells

Higher risk of GvHD due to HLA-mismatch which may require additional immunosuppressive therapy. Even with gene editing, this issue may persist as the final product is not 100% pure

Single-use therapy: the cells are administered once and then expand in the patient compared to regimens of chemotherapy

Potential worse CRS or NE side effects depend on the mismatch between donor and recipient which may require additional immunosuppressive therapy

May be available to patients who are ineligible for HSCT

Lymphodepleting chemotherapy is required to provide an environment for the CAR T-cells to expand. This makes the patients severely immunocompromised.

 

Patient may reject the allogeneic CAR T-cells

 

General CRS and NEs associated with CAR T administration

 

Currently, most trials are based in the United States (US) and China, with few in Europe and Japan, limiting the availability

 

Lack of clinical experience in this setting

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 Th1 and Tc1 cytokines
    • Proliferated
References
  1. Global Banking & Finance review. FDA Clears the IND for UCARTCS1, the First Allogeneic CAR-T to Treat Multiple Myeloma Patients. https://www.globalbankingandfinance.com/fda-clears-the-ind-for-ucartcs1-the-first-allogeneic-car-t-to-treat-multiple-myeloma-patients/ [accessed 2019 Apr 03]
  2. Graham C. et al. Allogeneic CAR-T cells: more than ease of access? Cells. 2018 Oct 01. DOI: 10.3390/cells7100155
  3. June C.H. and Sadelain M. Chimeric Antigen Receptor Therapy. N Eng J Med. 2018 Jul 5. DOI: 10.1056/NEJMra1706169
  4. U.S. Food & Drug Administration. KYMRIAH (tisagenlecleucel).https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm573706.htm [accessed 2019 Apr 04]
  5. U.S. Food & Drug Administration. YESCARTA (axicabtagene ciloleucel).https://www.fda.gov/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/ucm581222.htm [accessed 2019 Apr 04]
  6. Zhao W. H. et al. A phase I, open-label study of LCAR-B38M, a chimeric antigen receptor T cell therapy directed against B cell maturation antigen, in patients with relapse or refractory multiple myeloma. J Hematol Oncol. 2018 Dec 20; 11:141. DOI: 10.1186/s13045-018-0681-6.
  7. Cellectis. Manufacturing. http://www.cellectis.com/products/manufacturing [accessed 2019 Apr 04]
  8. Wohlfarth P. Worel N. and Hopfinger G. Chimeric antigen receptor T‑cell therapy—a hematological success story. Magazine of European Medical Oncology. 2018 Jun 06. DOI: 10.1007/s12254-018-0409-x
  9. The Quest for Off-the-Shelf CAR T Cells. Cancer Discovery. 2018 May 10. DOI: 10.1158/2159-8290.CD-ND2018-005
  10. Mathur R. et al. Universal SLAMF7-Specific CAR T-Cells As Treatment for Multiple Myeloma. Blood. 2017 Dec 07. http://www.bloodjournal.org/content/130/Suppl_1/502

Expert Opinion

CAR T-cells represent a promising therapy for hematological diseases, including multiple myeloma. Most clinical trials conducted with CAR T-cells in myeloma target BCMA, expressed on the surface of plasma cells, and CAR T-cells are autologous. There are some limitations derived from the fact that CAR T-cells are targeting BCMA so new targets need to be identified and also derived from the time required between apheresis of T-cells and the administration of CAR T-cells. In addition, there can be some manufacturing limitations. All these limitations may potentially affect clinical use.

The possibility of using allogeneic CAR T-cells may overcome these innate limitations, especially the lengthy vein-to-vein time, as well as the manufacturing problems. In addition, advantages in the efficacy can be also present because the allogeneic CAR T-cells use healthy donor T-cells and in the manufacturing process, editing strategies are feasible in order to improve the efficacy as well as to control and/or reduce the graft-versus-host disease potential.

Finally, the possibility of using different targets from BCMA, like CS1 or SLAMF7, will add more possibilities for the treatment of patients with myeloma because together with CAR T-cells, there are many bispecific and/or conjugated monoclonal antibodies, all of them targeting BCMA.

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