The number of cancer cell therapies has increased considerably over the last few years. 1There are several different types of cellular therapies, including chimeric antigen receptor (CAR) T cells, multiple tumor-associated antigen-specific T cells (TAA-T), natural killer (NK)-based therapies and T-cell therapies based on novel technologies like CRISPR. 1 Amongst the different types of cell therapies in development, approximately 50% are CAR T-cell therapies for various hematological malignancies and solid tumours.
At the 2019 meeting of the Society of Hematologic Oncology(SOHO), a series of talks was presented on the current advances and future potential of cellular therapies in hematological malignancies. Here we provide a summary of these talks with a focus on the latest treatment strategies, including CAR T cells and TAAs as well as NK- and CRISPR-based therapies.
CAR T therapies (ALL, NHL, MM, HL)
To date, two CAR T-cell therapies – tisagenlecleucel and axicabtagene ciloleucel (axi-cel) – have been approved by the European Medicines Agency(EMA) and U.S. Food and Drug Administration(FDA) for the treatment of hematological malignancies. Tisagenlecleucel is approved for the treatment of patients aged ≤25 years with relapsed/refractory (R/R) acute lymphocytic leukemia (ALL). Both tisagenlecleucel and axi-cel are approved for the treatment of patients with R/R large B-cell lymphoma. The safety and efficacy of axi-cel in the real-world setting has already been reportedand was comparable to the data obtained in the clinical trial setting ( ZUMA-1). 2
In patients aged ≤25 years with ALL, despite the high and deep remission rates seen with tisagenlecleucel in the ELIANA trial, approximately 40-50% of the patients relapsed within one year after infusion. If the relapse was soon after treatment it was usually due to CAR T cell loss, while 10-20% of late relapses were associated with CD19 antigen loss from the surface of leukemia cells. 2
In both the ALL and non-Hodgkin lymphoma (NHL) setting, CAR T-cell therapies have been associated with two main toxicities: cytokine release syndrome (CRS) and neurotoxicity. These safety concerns are not negligible and have led to death in some cases.
Multiple strategies are being investigated in order to reduce CAR T-mediated toxicity and increase relapse-free survival in R/R patients with ALL and NHL. For ALL, some of these strategies include the use of CAR T cells as bridging therapy for allogeneic stem cell transplantation, or in combination with checkpoint inhibitors in patients with early CAR T loss. Moreover, bi-specific CARs targeting CD19 and CD22, as well as dually transduced CARs with two separate lentiviral vectors (CD19- and CD22-specific) are also being investigated as a solution to the CD19 epitope loss seen in some patients with ALL. 2,3
In the R/R NHL setting, ³40–50% of patients will achieve durable complete response (CR) with CD19-directed CAR Ts. Taking this into consideration, along with the associated toxicities, one key question remains unanswered: will CAR T-cells ever replace autologous stem cell transplantation (ASCT) as the standard of care (SoC) in the future? At the moment, there are three phase III clinical trials ( ZUMA-7, BELINDA, TRANSFORM) comparing these two treatments in patients with R/R aggressive B cell NHL. The ZUMA-7 trial is expected to finish patient recruitment by the end of 2019.
CAR T-cell therapy has also been investigated for multiple myeloma (MM). Data from preclinical studies have suggested that bb2121, a CAR T construct targeting the B-cell maturation antigen (BCMA), shows promising activity in R/R MM. At the moment there are multiple BCMA CAR T trials ongoing, all using slightly different constructs. The most recent clinical efficacy data from these trials indicate good overall response rates (83-94%), variable CR rates (but always >50%) and low toxicity. 2BCMA CARs are still awaiting approval from the FDA and EMA.
For patients with Hodgkin lymphoma (HL), CAR T cells targeting CD30 have shown preclinical activity and are now being assessed in the phase I trial RELY-30for safety and preliminary efficacy in patients with R/R HL. The latest data from the trial indicate that CD30 CAR T cells have an acceptable safety profile, but, due to the short follow-up, response duration remains unknown. 2
Despite the exploding success of CAR T cells, there are major issues involving the cost as well as the time and infrastructure needed for CAR T manufacturing. At the current time the cost of CAR T is almost ten times higher than that of ASCT, which remains the SoC for patients with R/R B-cell malignancies. 2,4Many centers are trying to develop cell therapies with reduced manufacturing time and costs, as well as with reduced toxicity to allow outpatient therapy. One upcoming strategy that could potentially reduce the costs and eliminate the logistical hurdles is allogeneic ‘off-the-shelf’ CAR-T or CAR-NK therapy.
Allogeneic CAR therapies (allo-CAR)
Ewelina Morawafrom CRISPR Therapeutics, Cambridge, Massachusetts, US, introduced at SOHO 2019the off-the-shelf allogeneic CAR T construct that they have successfully manufactured and will soon clinically evaluate for safety and efficacy in patients with MM. 5Their approach involves extracting T cells from healthy donors ahead of the trial thereby bypassing the logistical limitations of using patient-derived cells. Moreover, it was highlighted that it is possible to obtain all the necessary CARs for one trial from a single healthy donor. This will not only reduce costs and manufacturing issues, but is thought to also provide more consistent and comparable results following infusion in multiple donors. 5Their BCMA-targeting CAR product was developed with the use of CRISPR-Cas9 technology. More specifically, the expression of the T-cell receptor (TCR) and beta-2 microglobulin (b2M) are disrupted by CRISPR/Cas 9 in order to prevent graft- versus-host disease (GvHD) and major histocompatibility complex (MHC-I) expression, respectively. With this method, they were able to knock out TCR and b2M in approximately 60% of the transduced cells, which remained healthy with no effects on their CD4:CD8 expression ratio. This construct, which is also known as CTX120, showed promising efficacy against solid tumors in vivoand will now be tested in clinical trials in MM. 5Another CRISPR-edited allo-CAR T that was developed by the same company, CTX110, is now in a clinical trialfor patients with R/R B-cell malignancies.
Another example of an allo-CAR T-cell therapy is the UCART19 product. This anti-CD19 TALEN-edited CAR T-cell construct was tested in first-in-human trials in adult ( CALM) and pediatric ( PALL) patients with R/R ALL. With the use of TALEN, both TCR and CD52 were knocked out in the engineered T cells, while MHC-I expression remained intact. From the pooled analysisof these two trials presented at ASH 2018, 21 patients with ALL were treated with UCART19 and 82% of FCA-treated (fludarabine, cyclophosphamide and alemtuzumab) patients achieved CR or CRi (CR with incomplete hematologic recovery) approximately a month after infusion. CRS was experienced in 19/21 patients with only one case being grade 4. Additionally, 2/21 patients experienced grade 1 skin GvHD. These results demonstrate that allo-CAR Ts show promise in the field of hematological malignancies and have opened the way for more research. 5,6
Another allo-CAR therapy that is currently being investigated is based on the use of CAR NKs. Katy Rezvanifrom the University of Texas MD Anderson Cancer Center, Houston, Texas, US, presented at SOHO 2019preliminary data from the use of allo-CAR NK cells to treat patients with R/R B-lymphoid malignancies (NHL, ALL, CLL). 7The first-in-human clinical trial (IND17321) assessed the safety and efficacy of this allo-CAR NK, with 8/11 patients achieving a clinical response and no CRS or neurotoxicity experienced to date. Moreover, the CAR NK cells could be detected for up to one year following infusion, which is attributed to the expression of proliferation-enhancing cytokines from the construct. The speaker also mentioned the advantages of using NK cells over T cells for CAR-based treatment as NK cells do not possess TCRs and thus do not need to be knocked out. However, infused NK cells seem to have limited persistence and they are not antigen-specific, unlike T cells. 7
All the above studies indicate the potential of allo-CAR therapies for the treatment of hematological malignancies. However, additional data are needed to validate these preliminary results and prospective comparative trials between allo- and auto-CARs are planned in the near future.
Not all about CARs - CTLs
Shifting the focus from CAR-based therapies, Ann Marie Leenfrom Baylor College of Medicine, Houston, Texas, US highlighted the potential of multi TAA-T cells for the treatment of hematological malignancies. 8This technology is based on selective resident T cells in the blood of each patient being isolated, activated and expanded ex vivoand then infused back to the same patient to enable their immune system to fight the disease. In this study, 33 patients with NHL or HL, either with active disease or after ASCT (TAA-T as adjuvant therapy), were infused with TAA-T cells that target multiple epitopes (CD4, CD8) in a four-step antigen escalation design. The preliminary data indicate that TAA-T cells have an acceptable safety profile and do not mediate any toxicity. Moreover, the investigators stated that multi TAA-T cells provide a feasible alternative cell therapy with clinical benefit as 14/18 patients who received TAA-T cells as adjuvant therapy to ASCT remain in long-term remission. Among the 15 patients with active disease, seven achieved CR. Further data are needed to validate this therapy, but initial results seem promising and indicate that TAA-T cells do manage to recruit the endogenous immune system of the patients. 8
It is evident that the future of cellular therapy is very bright for patients with hematological malignancies, as not only one, but multiple different strategies are under clinical investigation and show promising activity. CAR-based treatments remain at the center of cellular immunotherapy with new variations and adaptations being developed to tackle some of the associated toxicity and logistical hurdles seen with traditional CAR T-cell therapies.