2.1 Introduction
Adoptive cell therapy with gene-engineered T cells bearing antitumor-reactive T-cell receptor or chimeric antigen receptor (CAR) is a promising and rapidly evolving field of translational medicine. This approach has delivered exciting responses for some patients with lymphoid hematologic neoplasms, leading to recent US Food and Drug Administration approvals. Hematopoietic stem cellular gene therapy has also shown promising advances, with durable and potentially curative clinical benefit and without the potential toxicities of allogeneic hematopoietic cell transplant. However, for both of these novel strategies, many questions remain unanswered. Compared to synthetic viral gene addition therapy (e.g., CAR T-cell engineering), translation of gene-editing technologies to patient care is in its infancy. Multiple clinical trials are ongoing or expected to open for CAR T cell and inherited monogenic disorders (Gardner et al. 2017) (refer to subsequent disease-specific chapters in the book). In this chapter, we will highlight the most recent and clinically relevant developments in the arena of gene-modified T-cell-based therapies and hematopoietic stem cellular gene therapy specifically focusing on hematologic disorders. We will conclude the chapter by summarizing the apparent challenges and directions for the future.
2.2 Relapsed/Refractory B-Lineage Acute Lymphoblastic Leukemia
2.2.1 Children and Young Adults: CAR T Cells Show Promising Results
Transitioning CD19-directed CAR T cells from early-phase trials to a viable therapeutic approach with predictable efficacy and low toxicity for broad application is currently complicated by product heterogeneity resulting from (a) transduction of T cell of undefined subset composition, (b) variable efficiency of transgene expression, and (c) the effect of ex vivo culture on the differentiation state of the manufactured cells (Gardner et al. 2017; Rouce and Heslop 2017). Gardner et al. (2017) enrolled 45 children and young adults in PLAT-02 phase I trial with CD19+ relapsed or refractory B-lineage acute lymphoblastic leukemia (ALL). They used CD19 CAR product of defined CD4+/CD8+ (1:1 ratio) composition with uniform CAR expression and limited effector differentiation (described later). The rationale for this strategy comes from preclinical studies that suggest that a 1:1 ratio of CD4+ to CD8+ cells and culture with appropriate homeostatic cytokines would ensure maximum effectiveness of both T-cell subsets and would yield a less terminally differentiated T-cell population with maximum tumor killing capacity, prolonged CAR T-cell persistence, and the ability to retain memory and self-renewal capacity (Gardner et al. 2017; Rouce and Heslop 2017; Riddell et al. 2014). Products meeting all defined specifications could be manufactured in 93% of enrolled patients. The maximum tolerated dose (MTD) was 1x106 CAR T cells/kg (doses ranged from 0.5 to 10 × 106 cells/kg), and there were no deaths or instances of cerebral edema attributable to the product toxicity. The overall intent-to-treat minimal residual disease-negative (MRD-negative) remission rate was 89%. The MRD-negative remission rate was 93% in all patients who received a CAR T-cell product and 100% in the subset of patients who received fludarabine (Flu) and cyclophosphamide (Cy) lymphodepletion. Twenty-three percent of patients developed reversible CRS and/or reversible but severe neurotoxicity. No deaths resulting from toxicities were reported. These data demonstrate that manufacturing a defined composition CD19 CAR T cell identifies an optimal cell dose with highly potent antitumor activity and a tolerable adverse effect (AEs) profile in a cohort of patients with an otherwise poor prognosis. This manufacturing platform therefore provides a significant advantage over prior reported trials (see Chaps. 4 and 5). The observation that 100% of patients receiving Flu/Cy lymphodepletion had an MRD-negative remission further reinforces the importance of lymphodepletion regimens that include Flu, as opposed to Cy alone (Gardner et al. 2017; Turtle et al. 2016) (see Chap. 4).
2.2.2 Children and Young Adults: Tisagenlecleucel (CTL019) and Its US FDA Approval1 (2017)
On August 30, 2017, the US FDA granted approval to tisagenlecleucel for the treatment of patients up to age 25 years with B-cell precursor ALL that is refractory or in second or later relapse (see footnote 1). Approval of tisagenlecleucel was based on a phase II single-arm trial (ELIANA; NCT02435849) of 63 patients with relapsed or refractory pediatric precursor B-cell ALL, including 35 patients who had a prior hematopoietic cell transplantation (Buechner et al. 2017). Median age of the participants was 12 years (range, 3–23 years). Noteworthy, during the presentation of updated results of this global multicenter ELIANA trial at European Hematology Association (EHA®) 2017, it was reported that as of November 2016, 88 patients were enrolled. There were seven (8%) manufacturing failures, nine (10%) patients were not infused due to death or AEs, and four patients (5%) were pending infusion at the time of data cutoff. All patients received a single dose of tisagenlecleucel intravenously within 2–14 days following the completion of lymphodepleting chemotherapy. Of the 63 patients who were evaluable for efficacy, the confirmed overall remission rate as assessed by independent central review was 82.5% (95% CI 70.9, 91.0), consisting of 63% of patients with complete remission (CR) and 19% with CR with incomplete hematological recovery (CRi). All patients with a confirmed CR or CRi were MRD-negative by flow cytometry (FC) method. Median remission duration was not reached (range: 1.2 to 14.1+ months). Grade III or IV AEs were noted in 84% of patients. Serious adverse reactions such as CRS, including fatal CRS and CRS-associated disseminated intravascular coagulation with intracranial hemorrhage, prolonged cytopenias, infection, cardiac failure, and cardiac arrest occurred in patients receiving tisagenlecleucel. FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (see footnote 1). The recommended tisagenlecleucel dose is one infusion of 0.2–5.0 × 106 (CAR)-positive viable T cells/kg body weight intravenously for patients who are less than or equal to 50 kg and 0.1–2.5 × 108 total CAR-positive viable T cells intravenously for patients who are >50 kg, administered 2–14 days after lymphodepleting chemotherapy (see footnote 1) (Buechner et al. 2017) (see Chap. 4).
2.2.3 Adults with Relapsed/Refractory B-ALL: Phase I Trial from Memorial Sloan Kettering Cancer Center (MSKCC)
Park et al. (2018) enrolled 83 adult (age range, 23–74 years) patients with relapsed B-cell ALL, of whom 53 who received an infusion of anti-CD19 autologous T cells costimulated with CD28. A total of 78 patients underwent leukapheresis, 11 of whom did not undergo an attempt at cell production (owing to death or the receipt of alternative treatment), and 13 did not have cells infused (2 because of production failure and 11 owing to infection, alternative treatment, or death). A total of 36 patients (68%) received CAR T-cell therapy as a third or later salvage treatment, 12 (23%) had primary refractory disease, 19 (36%) had undergone allogeneic hematopoietic cell transplantation (allo-HCT) previously, and 13 (25%) had received blinatumomab previously. A total of 16 patients (30%) had Philadelphia chromosome-positive ALL, including 5 patients with the T315I ABL kinase mutation. Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics. After infusion, severe CRS occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15–40); 1 patient died. CR was observed in 83% of the patients. At a median follow-up of 29 months (range, 1–65), the median event-free survival (EFS) was 6.1 months (95% CI, 5.0–11.5), and the median overall survival (OS) was 12.9 months (95% CI, 8.7–23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median EFS of 10.6 months (95% CI, 5.9 to not reached) and a median OS of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the CRS and neurotoxic events and shorter long-term survival than did patients with a low disease burden (Gardner et al. 2017). The latter observation was also made by Maude et al. (2014) (see Chap. 5).
2.3 Non-Hodgkin B-Cell Lymphomas
2.3.1 Phase I, ZUMA-1 Study (Locke et al. 2017a): Primary Results of Axicabtagene Ciloleucel (KTE-C19) with a Focus on Refractory Diffuse Large B-Cell Lymphoma (DLBCL)
In the phase I multicenter ZUMA-1 study, Locke et al. (2017a) evaluated KTE-C19, an autologous CD28-costimulated CAR T-cell therapy, in patients with refractory DLBCL. Patients received concurrent cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days followed by KTE-C19 at a target dose of 2 × 106 CAR T cells/kg of recipient weight. The incidence of dose-limiting toxicity (DLT) was the primary endpoint. Seven patients were treated with KTE-C19, and one patient experienced a DLT of grade IV CRS and neurotoxicity. Grade ≥ III CRS and neurotoxicity were observed in 14% (n = 1 of 7) and 57% (n = 4 of 7) of patients, respectively. All other KTE-C19-related grade ≥III events resolved within 1 month. The overall response rate (ORR) was 71% (n = 5 of 7), and CR rate was 57% (n = 4 of 7). Three patients have ongoing CR (all at 12+ months) at the time of publication. CAR T cells demonstrated peak expansion within 2 weeks and continued to be detectable at 12+ months in patients with ongoing CR. Consistent with the on-target, off-tumor effect of KTE-C19, B-cell aplasia and hypogammaglobulinemia were observed in subjects with ongoing CR and persistent CAR T cells at 12 months post-infusion. This multicenter study validated that centralized manufacturing is feasible and established the logistics for transportation of patient-specific product door to door within approximately 2 weeks (Locke et al. 2017a; Lulla and Ramos 2017) (see Chap. 6).
2.3.2 Additional Results of ZUMA-1 Study (Locke et al. 2017b) and US FDA Approval2 (2017) of Axicabtagene Ciloleucel (KTE-C19)
The safety and efficacy of axicabtagene ciloleucel were established in a multicenter ZUMA-1 clinical trial of 101 adult patients with refractory or relapsed large B-cell lymphoma (Locke et al. 2017a, b). In the subsequent report data from patients enrolled into two cohorts consisting of DLBCL (cohort 1) and primary mediastinal B-cell lymphoma (PMBCL) or transformed follicular lymphoma (TFL) (cohort 2) were reported (Locke et al. 2017b). All patients had chemorefractory disease, with roughly 80% refractory to their last line of chemotherapy, and the remainder relapsing within 12 months of autologous hematopoietic cell transplant (auto-HCT). Patients had received a median of three prior therapies. Prior to infusion of axicabtagene ciloleucel, a conditioning regimen of Flu/Cy was administered. Axicabtagene ciloleucel was administered as a single infusion of modified autologous T cells at a target dose of 2 × 106 CAR+ T cells/kg of recipient weight. The median follow-up for the primary analysis was 8.7 months, with most patients having data available for 6 months. There were four patients who experienced a CR but did not have assessment data available for 6 months. For the primary analysis, these individuals were classified as nonresponders, suggesting the response rates could be higher. The primary endpoint of the phase II study was ORR, which was significantly satisfied across the full study (P < 0.0001). After 6 months, 41% of patients were still in response, with a CR rate of 36% and a partial response (PR) rate of 5%. There was one incidence of a PR improving to a CR after 9 months, suggesting longer follow-up could further alter these numbers. Across the full duration of the study, those with DLBCL (n = 77) had an ORR of 82% and a CR rate of 49%. In the PMBCL/TFL group (n = 24), the ORR was 83% and the CR rate was 71%. After 6 months of follow-up, the ORR in the DLBCL group was 36%, which included a CR rate of 31%. In the PMBCL/TFL group, the 6-month ORR rate was 54%, with a CR rate of 50%. Median OS was not yet reached. The most common grade ≥ III AEs were anemia (43%), neutropenia (39%), decreased neutrophil count (32%), febrile neutropenia (31%), decreased white blood cell count (29%), thrombocytopenia (24%), encephalopathy (21%), and decreased lymphocyte count (20%). There were three fatal events in the study, two of which were deemed related to axicabtagene ciloleucel: hemophagocytic lymphohistiocytosis (HLH) and cardiac arrest in the setting of CRS. The third death was from pulmonary embolism. Data from 93 patients were available for the interim analysis from the ZUMA-1 trial (Locke et al. 2017a), whereas the primary assessment contained data for 101 patients (Locke et al. 2017b). With more patients assessed, the rate of CRS declined from 18% at the interim assessment to 13% for the primary analysis. Additionally, neurologic events dropped from 34% in the interim analysis to 28% in the primary assessment. There were no cases of cerebral edema. On the basis of these results, US FDA approved axicabtagene ciloleucel, for use in adult patients with certain types of large B-cell lymphoma after at least two other kinds of treatment have failed, including DLBCL, PMBCL, and DLBCL arising from TFL (see footnote 2). Notably, patients with primary central nervous system lymphoma were excluded from receiving axicabtagene ciloleucel, and the drug is not approved for treatment of patients with this condition.
2.3.3 Phase II Results of ZUMA-1 Study (Neelapu et al. 2017): Axicabtagene Ciloleucel in DLBCL, PMBCL, and Transformed FL
In a multicenter, phase II study, Neelapu et al. (2017) enrolled 111 patients with DLBCL, PMBCL, and TFL who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2 × 106 anti-CD19 CAR T cells/kg of recipient body weight after receiving a conditioning regimen of low-dose Flu/Cy. The primary end point was the rate of objective response (calculated as the combined rates of CR and PR). Secondary end points included OS, safety, and biomarker assessments. Among the 111 patients who were enrolled, axicabtagene ciloleucel was successfully manufactured for 110 (99%) and administered to 101 (91%) patients. The objective response rate was 82%, and the CR rate was 54%. These findings compare favorably with the results of the recent SCHOLAR-1 study (Crump et al. 2017) of conventional therapies for this disease, which showed an objective response rate of 26% and a complete response rate of 7%. With a median follow-up of 15.4 months, 42% of the patients were still in response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common AEs of grade III or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade III or higher CRS and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. In this particular study, higher CAR T-cell levels in blood were associated with response. Furthermore, this study (Neelapu et al. 2017) confirmed the feasibility and reliability of centralized manufacturing and coordination of leukapheresis procedures and shipping from multiple centers across the country. The product was manufactured for 99% of the enrolled patients and was administered to 91%. The short 17-day median turnaround time may be important for these patients with refractory large B-cell lymphoma, who generally have rapidly growing disease. The investigators of this multicenter trial (Neelapu et al. 2017) also reported that axicabtagene ciloleucel could be administered safely at medical facilities that perform transplantation, even if such centers had no specific experience in CAR T-cell therapy.
2.3.4 Tisagenlecleucel (CTL019) in Relapsed/Refractory DLBCL and Follicular Lymphoma: Results from University of Pennsylvania (UPenn) (Schuster et al. 2017a)
Patients with DLBCL or FL that is refractory to or which relapses after immunochemotherapy and transplantation have a poor prognosis. High response rates have been reported with the use of T cells modified by CAR that target CD19 in B-cell cancers (Grupp et al. 2013; Porter et al. 2011), although data regarding B-cell lymphomas are limited to small number of patients. Schuster et al. (2017a) used autologous T cells that express a 41BB-costimulated CD19-directed CAR (CTL019) to treat patients with DLBCL or FL that had relapsed or was refractory to previous treatments. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CTL019 cells in vivo, and immune recovery. A total of 38 patients were enrolled. Twenty-eight patients received tisagenlecleucel, and 18 of 28 had a response (64%; 95% CI, 44–81). CR occurred in 6 of 14 patients with DLBCL (43%; 95% CI, 18–71) and 10 of 14 patients with follicular lymphoma (71%; 95% CI, 42–92). CTL019 cells proliferated in vivo and were detectable in the blood and bone marrow of patients regardless of ultimate response status. Sustained remissions were achieved, and at a median follow-up of 28.6 months, 86% of patients with DLBCL who had a response (95% CI, 33–98) and 89% of patients with FL who had a response (95% CI, 43–98) had maintained the response. In this particular study (Schuster et al. 2017a), the CRS was less frequent and less severe than previously reported for the use of tisagenlecleucel in the treatment of ALL and chronic lymphocytic leukemia (CLL) (Grupp et al. 2013; Porter et al. 2011). The CRS was self-limiting and its severity was not correlated with response to therapy. Severe CRS occurred in five patients (18%). Serious encephalopathy occurred in three patients (11%); two cases were self-limiting and one case was fatal. All patients in CR by 6 months remained in remission at 7.7–37.9 months (median, 29.3 months) after induction, with recovery of normal B cells in 8 of 16 patients and with improvement in levels of IgG in 4 of 10 patients and of IgM in 6 of 10 patients at 6 months or later and in levels of IgA in 3 of 10 patients at 18 months or later. Transient encephalopathy developed in approximately one in three patients and severe CRS developed in one of five patients.
2.3.5 US FDA Approval (2018) of Tisagenlecleucel3 (CTL019) for Adults with Relapsed/Refractory Large B-Cell Lymphoma: Results of JULIET Study (Schuster et al. 2017b, c)
On May 1, 2018, the US FDA approved tisagenlecleucel, a CD19-directed genetically modified autologous T-cell immunotherapy, for adults with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy including DLBCL not otherwise specified (DLBCL-NOS), high-grade B-cell lymphoma, and DLBCL arising from FL (transformed lymphoma) (see footnote 3). Approval was based on a single-arm, open-label, and multicenter, phase II trial (Schuster et al. 2017b) in adults with relapsed or refractory DLBCL and DLBCL after transformation from FL. Eligible patients must have been treated with at least two prior lines of therapy, including an anthracycline and rituximab, or relapsed following auto-HCT. Patients received a single infusion of tisagenlecleucel following completion of lymphodepleting chemotherapy (Flu 25 mg/m2, Cy 250 mg/m2/day × 3 days or bendamustine 90 mg/m2/day × 2 days). The ORR as assessed by an independent review committee for the 68 evaluable patients [presented at multiple national meetings in 2017 (Schuster et al. 2017b, c)] was 50% (95% CI: 37.6, 62.4) with a complete response rate of 32% (95% CI: 21.5, 44.8). With a median follow-up time of 9.4 months, the duration of response was longer in patients with a best overall response of CR, as compared to a best overall response of PR. Among patients achieving CR, the estimated median duration of response was not reached (95% CI: 10.0 months, not estimable). The estimated median response duration among patients in PR was 3.4 months (95% CI: 1.0, not estimable). The most common adverse reactions (incidence >20%) in patients on the trial were CRS, infections-pathogen unspecified, pyrexia, diarrhea, nausea, fatigue, hypotension, edema, and headache. Because of the serious risks of CRS and neurologic toxicities, FDA approved tisagenlecleucel with a Risk Evaluation and Mitigation Strategy (see footnote 3). The recommended dose of tisagenlecleucel for relapsed or refractory adult DLBCL is 0.6–6.0 × 108 CAR+ viable T cells (see footnote 3). Like axicabtagene ciloleucel, tisagenlecleucel is also not indicated for the treatment of patients with primary central nervous system lymphoma.
2.3.6 Long Duration of CR in DLBCL After Anti-CD19 CAR T-Cell Therapy: Data from the NCI (Kochenderfer et al. 2017)
Kochenderfer et al. (2017) administered anti-CD19 CAR T cells preceded by Flu/Cy conditioning chemotherapy to patients with relapsed DLBCL. Five of the seven evaluable patients obtained CRs. Four of the five complete remissions had long-term durability with durations of remission of 56, 51, 44, and 38 months; to date (Gardner et al. 2017), none of these four cases of lymphomas have relapsed. Importantly, CRs continued after recovery of nonmalignant polyclonal B cells in three of four patients with long-term CRs. In these three patients, recovery of CD19+ polyclonal B cells took place 28, 38, and 28 months prior to the last follow-up, and each of these three patients remained in CR at the last follow-up. Nonmalignant CD19+ B-cell recovery with continuing complete remissions demonstrated that remissions of DLBCL can continue after the disappearance of functionally effective anti-CD19 CAR T-cell populations. Patients had a low incidence of severe infections despite long periods of B-cell depletion and hypogammaglobulinemia. Only one hospitalization for an infection occurred among the four patients with long-term CRs. Thus, anti-CD19 CAR T cells caused long-term remissions of chemotherapy-refractory DLBCL without substantial chronic toxicities.
2.4 Chronic Lymphocytic Leukemia
2.4.1 CLL and Anti-CD19 CAR T Cells Following Ibrutinib Failure
Turtle et al. (2017) evaluated the safety and feasibility of anti-CD19 CAR T-cell therapy in patients with CLL who had previously received ibrutinib. Twenty-four patients with CLL received lymphodepleting chemotherapy and anti-CD19 CAR T cells at one of three dose levels (2 × 105, 2 × 106, or 2 × 107 CAR T cells/kg). Nineteen patients experienced disease progression while receiving ibrutinib, three were ibrutinib intolerant, and two did not experience progression while receiving ibrutinib. Six patients were venetoclax-refractory, and 23 had a complex karyotype and/or 17p deletion. Four weeks after CAR T-cell infusion, the ORR by International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria was 71% (17 of 24). Twenty patients (83%) developed CRS, and eight (33%) developed neurotoxicity, which was reversible in all but one patient with a fatal outcome. Twenty of 24 patients received Flu/Cy lymphodepletion and CD19 CAR T cells at or below the MTD (≤ 2 × 106 CAR T cells/kg). In 19 of these patients who were restaged, the ORR by IWCLL imaging criteria 4 weeks after infusion was 74% (CR, 4 of 19, 21%; PR, 10 of 19, 53%), and 15 of 17 patients (88%) with marrow disease before CAR T cells had no disease by FC after CAR T cells. Twelve of these patients underwent deep IGH sequencing, and seven (58%) had no malignant IGH sequences detected in marrow. The absence of the malignant IGH clone in marrow of patients with CLL who responded by IWCLL criteria was associated with 100% PFS and OS (median 6.6 months follow-up) after CAR T-cell immunotherapy. The PFS was similar in patients with lymph node PR or CR by IWCLL criteria. CD19 CAR T cells were highly effective with manageable toxicity in patients with high-risk CLL, including those who were ibrutinib-refractory. Of note, although bone marrow disease was highly responsive to CAR T cells, complete elimination of bulky nodal disease was less common, suggesting the malignant lymph node environment may impair CAR T-cell infiltration and/or function. Thus, CR rates in advanced CLL might be improved if CAR T-cell immunotherapy is delivered when ibrutinib-induced mobilization of lymph node disease into blood and/or marrow is still effective and before the development of bulky lymphadenopathy (Gill et al. 2017). Such a strategy might be used by monitoring patients receiving ibrutinib for development of ibrutinib-resistant mutations or other early evidence of progression (see Chaps. 5 and 6).
2.5 Multiple Myeloma
2.5.1 Results of Anti-BCMA CAR T Cells: Data from NCI (Ali et al. 2016; Brudno et al. 2017)
B-cell maturation antigen (BCMA) is expressed in most cases of MM. Ali et al. (2016) from NCI conducted the first-in-human clinical trial of CAR T cells targeting BCMA. T cells expressing the CAR used in this work (CAR-BCMA) specifically recognized BCMA-expressing cells. The anti-BCMA CAR used in this work incorporated the 11D-5-3 anti-BCMA single-chain variable fragment (scFv), a CD28 costimulatory domain, and the CD3−ζ T-cell activation domain. The cells were transduced with a γ-retroviral vector, and 9 days after the initiation of cultures, CAR-BCMA T cells were infused. Twelve patients received CAR-BCMA T cells in this dose escalation trial. The dose escalation plan called for an initial dose of 0.3 × 106 CAR+ T cells/kg with threefold increase to each subsequent dose level. Among the six patients treated on the lowest two dose levels, limited antimyeloma activity and mild toxicity occurred. On the third dose level, one patient obtained a very good partial remission (VGPR). Two patients were treated on the fourth dose level of 9 × 106 CAR T cells/kg body weight. Before treatment, the first patient on the fourth dose level had chemotherapy-resistant MM, making up 90% of bone marrow cells. After treatment, plasma cells in the marrow became undetectable by FC, and the patient’s MM entered a stringent complete remission (sCR) that lasted for 17 weeks before relapse. The second patient on the fourth dose level had chemotherapy-resistant MM making up 80% of bone marrow cells before treatment. Twenty-eight weeks after this patient received CAR-BCMA T cells, bone marrow plasma cells were undetectable by FC, and the serum monoclonal protein had decreased by >95%. Both patients treated on the fourth dose level had toxicity consistent with CRS including fever, hypotension, and dyspnea. Both patients had prolonged cytopenias. Serum BCMA (sBCMA) served as a tumor marker because substantial decreases in sBCMA occurred in the three patients with the most impressive antimyeloma responses.
Most recently (ASH® annual meeting 2017), the same group presented their updated data of 13 patients treated to date on the highest dose level of 9 × 106 CAR-BCMA T cells/kg (Brudno et al. 2017). The median age of the 13 patients was 54 years (range 43–66). The patients had a median of 11 prior lines of therapy. Five patients (12, 19, 20, 23, and 25) had a chromosome 17p deletion prior to protocol enrollment. Toxicities were consistent with prior reports of CRS after infusions of CAR T cells. Of 13 patients, 4 received the interleukin (IL)-6-receptor antagonist tocilizumab to treat CRS; 2 of these 4 patients also received corticosteroids. While CAR-BCMA T-cell toxicity was severe in some cases, the toxicities were mainly limited to the first 2 weeks after CAR-BCMA T-cell infusion. Because of grade III/IV CRS experienced by some patients with high bone marrow myeloma burdens, investigators of this study modified the clinical protocol to only allow enrollment of patients with lower myeloma burdens defined as MM making up 30% or less of bone marrow cells. Two patients (16 and 18) experienced delayed neutropenia and thrombocytopenia that started approximately 1 month after CAR T-cell infusion when blood counts had recovered from the chemotherapy administered before CAR-BCMA T-cell infusions. These patients were treated with filgrastim, eltrombopag, and prednisone based on the hypothesis that the cytopenias were caused by CAR T cells in the patient’s bone marrow. In both cases, cytopenias resolved after approximately 1 month. CAR-BCMA T cells exhibited clear antimyeloma activity. Nine of 11 evaluable patients obtained objective antimyeloma responses with 2 stringent complete responses, 5 very good partial responses, and 2 partial responses; the duration of responses varied. The longest response to date is 66 weeks. Eight of ten evaluable patients obtained MRD-negative status by bone marrow flow cytometry. Consistent with BCMA-specific T-cell activity, plasma cells were reduced on bone marrow core biopsies in all eight evaluated patients and absent in four of these patients 2–3 months after CAR-BCMA T-cell infusion. CAR+ cell levels have been quantified in the blood of patients. CAR T-cell levels peaked in the first 2 weeks after infusion and persisted at lower levels for many months in some cases. Cytokines were measured in the serum of all patients. In patients with CRS, multiple cytokines including interferon-γ, IL-6, IL-8, and IL-17A were consistently elevated in the serum. Accrual to this trial continues. Toxicity was significant but limited in duration and controllable (Rouce and Heslop 2017).
2.5.2 Anti-BCMA CAR T Cells: Data Presented at ASH® 2017 by UPenn (Cohen et al. 2017)
Cohen and coworkers reported early safety and clinical activity of CART-BCMA without lymphodepleting chemotherapy in highly refractory MM patients during ASH® 2016 (Cohen et al. 2016). Subsequently, they reported extended results from this initial cohort, as well as initial safety and efficacy in additional cohorts at two dose levels in conjunction with Cy at ASH® 2017 (Cohen et al. 2017). Three cohorts are being enrolled: (1) 1–5 × 108 CAR T cells alone; (2) Cy 1.5 g/m2 + 1–5 × 107 CAR T cells; and (3) Cy 1.5 g/m2 + 1–5 × 108 CART cells. CART-BCMA cells are given as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2), with Cy given on day 3. Participants need serum creatinine (Cr) <2.5 mg/dL or Cr clearance ≥30 mL/min; adequate hepatic, cardiac, and pulmonary function; and absolute CD3 count ≥150/μL. BCMA expression on MM cells is assessed but not required for eligibility. CAR T-BCMA expansion/persistence is assessed by flow cytometry and qPCR. Soluble BCMA levels are measured by ELISA. Responses are assessed by IMWG criteria. As of June 24, 17, 33 patients have consented, with 28 eligible, 21 infused, 4 awaiting infusion, and 3 manufactured but never treated due to rapid progression/clinical deterioration. Of treated patients (n = 21), nine are in cohort 1, five in cohort 2, and seven in cohort 3. Median age is 57 (range 44–73), 71% male, and median 4.3 years from diagnosis. Median lines of therapy is 7 (range 3–11); 100% are proteasome inhibitor and immunomodulatory drugs-refractory, 67% daratumumab-refractory. Ninety-five percent had high-risk cytogenetics, 67% del17p or TP53 mutation, and 29% extramedullary disease. All expressed BCMA on MM cells and received the minimum target dose of CAR T-BCMA, with 18 patients (86%) receiving full-planned dose and 3 patients receiving 40% of dose (third infusion held due to fevers). Toxicities in cohort 1 (n = 9) were previously reported and included CRS in eight patients (three grade III/IV, with four receiving tocilizumab) and neurotoxicity (grade IV encephalopathy) in two patients. In cohorts 2 and 3 (n = 12), CRS has occurred in nine patients (three grade III, zero grade IV, none requiring tocilizumab) and neurotoxicity in 1 patient (grade II confusion/aphasia), with no unexpected/DLTs and no TRM. Regarding efficacy, in cohort 1 six of nine patients responded (one stringent CR [sCR], two VGPR, one PR, two MR), with one ongoing sCR at 21 months and other responses lasting 1.5–5 months. In cohort 2, with Cy but tenfold lower CAR T dose, two of five patients responded (one PR, one MR) but progressed at 4 and 2 months, respectively. In cohort 3, median follow-up is currently 1 month, with five of six patients responding (one CR, three PR, one MR) and one not yet evaluable. All patients had detectable CAR T-BCMA expansion by qPCR, and 90% were detectable by FC, with preferential expansion of CD8+ cells and similar degree of expansion in blood and marrow. Median peak expansion (as measured by copies/μg DNA) is 6160, 14,761, and 45,268 in cohorts 1, 2, and 3, respectively, suggesting a benefit with adding Cy, though this was not statistically significant. Achieving PR or better is associated with higher peak CART-BCMA levels and decline in soluble BCMA, but not with baseline soluble BCMA level or intensity of baseline BCMA expression by flow on MM cells. Serial marrow FC demonstrates that five of six patients with ≥PR and detectable residual MM cells have decreased BCMA intensity on MM cells post-infusion compared with baseline. CART-BCMA infusions following Cy lymphodepletion are feasible and have significant clinical activity in highly refractory MM patients with poor-risk genetics and limited treatment options. Efficacy appears lower at the 107 dose, compared with 108, and remaining patients are now being enrolled in cohort 3. CRS remains a common but manageable toxicity. Decreased BCMA expression on residual MM cells post-infusion may be an escape mechanism reflecting CART-BCMA-induced immune editing. These data also provide further support for exploration of CART-BCMA in relapsed/refractory MM.
2.5.3 CRB-401: A Multicenter Trial Phase I Dose Escalation Trial of bb2121
Berdeja et al. (2017) assessed safety and efficacy of the CAR T-cell modality in relapsed and refractory MM (RRMM), by designing a CAR construct targeting BCMA. They reported the data at ASH® 2017. The bb2121 consists of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB costimulatory motif, and a CD3-zeta T-cell activation domain. CRB-401 (NCT02658929) is a two part, multicenter phase I dose escalation trial of bb2121 in patients with relapsed and refractory MM (RRMM) who have received ≥3 prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have ≥50% BCMA expression on clonal plasma cells. Peripheral blood mononuclear cells are collected via leukapheresis and shipped to a central facility for transduction, expansion, and release testing prior to being returned to the site for infusion. Patients undergo lymphodepletion with Flu (30 mg/m2) and Cy (300 mg/m2) daily for 3 days and then receive one infusion of bb2121. The study follows a standard 3 + 3 design with planned dose levels of 50, 150, 450, 800, and 1200 × 106 CAR+ T cells. The primary outcome measure is incidence of AEs, including DLTs. Additional outcome measures were quality and duration of clinical response assessed according to the IMWG Uniform Response Criteria for Multiple Myeloma, evaluation of MRD, overall and PFS, quantification of bb2121 in blood, and quantification of circulating soluble BCMA over time. As of May 4, 2017, 21 patients (median age 58 [37–74]) with a median of 5 [1–16] years since MM diagnosis had been infused with bb2121, and 18 patients were evaluable for initial (1-month) clinical response. Patients had a median of 7 prior lines of therapy (range 3–14), all with prior auto-HCT; 67% had high-risk cytogenetics. Fifteen of 21 (71%) had prior exposure to, and 6 of 21 (29%) were refractory to 5 prior therapies (bortezomib/lenalidomide/carfilzomib/pomalidomide/daratumumab). Median follow-up after bb2121 infusion was 15.4 weeks (range 1.4–54.4 weeks). As of data cutoff, no DLTs and no treatment-emergent grade III or higher neurotoxicities similar to those reported in other CAR T clinical studies had been observed. CRS, primarily grade I or II, was reported in 15 of 21 (71%) patients: 2 patients had grade III CRS that resolved in 24 h, and 4 patients received tocilizumab, 1 with steroids, to manage CRS. CRS was more common in the higher-dose groups but did not appear related to tumor burden. One death on study, due to cardiopulmonary arrest more than 4 months after bb2121 infusion in a patient with an extensive cardiac history, was observed while the patient was in sCR and was assessed as unrelated to bb2121. The ORR was 89% and increased to 100% for patients treated with doses of 1.5 × 108 CAR+ T cells or higher. No patients treated with doses of 1.50 × 108 CAR+ T cells or higher had disease progression, with time since bb2121 between 8 and 54 weeks. MRD-negative results were obtained in all four patients evaluable for analysis. CAR+ T-cell expansion has been demonstrated consistently and three of five patients evaluable for CAR+ cells at 6 months had detectable vector copies. The ORR was 100% at these dose levels with eight ongoing clinical responses at 6 months and one patient demonstrating a sustained response beyond 1 year.
2.5.4 Data from China with Unique Antigen-Binding Domain: Late Breaking Abstract at ASCO® 2017
Fan et al. (2018) reported results using a CAR T designated LCAR-B38M CAR T, which targets two different epitopes on BCMA and induce selective toxicity in BCMA-expressing tumor cells.4 A single-arm clinical trial was conducted to assess safety and efficacy of this approach. A total of 19 patients with RRMM were included in the trial. The median number of infused cells was 4.7 (0.6–7.0) × 106/kg. The median follow-up was 208 (62–321) days. Among the 19 patients who completed the infusion, 7 patients were monitored for a period of more than 6 months. Six out of the seven achieved CR- and MRD-negative status. The 12 patients who were followed up for less than 6 months met near CR criteria of modified EBMT criteria for various degrees of positive immunofixation. All these effects were observed with a progressive decrease of M-protein and thus may eventually meet CR criteria. In the most recent follow-up examination, all 18 surviving patients were determined to be free of myeloma-related biochemical and hematologic abnormalities. CRS was observed in 14 (74%) patients who received treatment. Among these 14 patients, there were 9 cases of grade I, 2 cases of grade II, 1 case of grade III, and 1 case of grade IV patient who recovered after treatments. A 100% objective response rate (ORR) to LCAR-B38M CAR T cells was observed. Of 18 out of 19 (95%) patients reached CR or near CR status without a single event of relapse in a median follow-up of 6 months. The majority (see footnote 1) of the patients experienced mild or manageable CRS (Gardner et al. 2017).
2.6 Classic Hodgkin and Anaplastic Large-Cell Lymphomas
2.6.1 CD30-Directed CAR T Cell: Phase I Study in Patients with Relapsed/Refractory Classic Hodgkin Lymphoma (cHL) and Anaplastic Large-Cell Lymphoma (ALCL)
In an open-label, phase I study, Wang et al. (2017) reported results of 18 patients including 1 with primary cutaneous ALCL and 17 with cHL. All patients received a conditioning chemotherapy (three regimen options) followed by the CAR T-cell infusion. The level of CAR transgenes in peripheral blood and biopsied tumor tissues was measured periodically according to an assigned protocol by quantitative PCR (qPCR). Eighteen patients were enrolled; most of whom were heavily pre-treated or had extensive disease and received a mean of 1.56 × 107 CAR-positive T cell/kg (SD, 0.25; range, 1.1–2.1) in total during infusion. CAR T-cell infusion was tolerated, with grade ≥3 toxicities occurring only in 2 of 18 patients. Of 18 patients, 7 achieved partial remission and 6 achieved stable disease. An inconsistent response of lymphoma was observed: lymph nodes presented a better response than extranodal lesions, and the response of lung lesions seemed to be relatively poor. Lymphocyte recovery accompanied by an increase of circulating CAR T cells (peaking between 3 and 9 days after infusion) is a probable indictor of clinical response. Analysis of biopsied tissues by qPCR and immunohistochemistry revealed the trafficking of CAR T cells into the targeted sites and reduction of the expression of CD30 in tumors. The investigators concluded that future clinical trial protocols need to consider the further optimization of conditioning regimens, the trial of multiple-cycle infusions of CAR T cells, and intervention of the CAR T-cell protocol in the early-disease stage.
2.6.2 CD30-Directed CAR T Cell: Another Phase I Study in Patients with Relapsed/Refractory cHL and ALCL
Subsequently, Ramos et al. (2017) conducted a phase I dose escalation study in which nine patients have relapsed/refractory EBV-negative cHL (n = 6 plus one patient with composite lymphoma [diffuse large B-cell lymphoma evolved to Hodgkin lymphoma]) and ALCL (n = 2; one patient had cutaneous anaplastic lymphoma kinase-negative and one patient had anaplastic lymphoma kinase-positive systemic ALCL). The patients were infused with autologous T cells that were gene-modified with a retroviral vector to express the CD30-specific CAR T cell encoding the CD28 costimulatory endodomain. Three dose levels, from 0.2 × 108 to 2 × 108 CAR T cell/m2, were infused without a conditioning regimen. All other therapy for malignancy was discontinued at least 4 weeks before CAR T-cell infusion. Seven patients had previously experienced disease progression while being treated with brentuximab. No toxicities attributable to CAR T cells were observed. Of seven patients with relapsed cHL, one entered CR lasting more than 2.5 years after the second infusion of CAR T cells, one remained in continued CR for almost 2 years, and three had transient stable disease. Of two patients with ALCL, one had a CR that persisted 9 months after the fourth infusion of CAR T cells. The expansion of CAR T cells in peripheral blood peaked 1 week after infusion, and CAR T cells remained detectable for over 6 weeks. Although CD30 may also be expressed by normal activated T cells, no patients developed impaired virus-specific immunity. The study concluded that appropriate tumor reduction and lymphodepletion before CAR T-cell infusion should enhance their clinical activity without increasing toxicity. Since inhibition of PD1 is an appropriate option in patients with relapsed HL (Ansell et al. 2015), future exploration of the synergy between CAR T cell directed against CD30 and PD1/PD-L1 blockade seems interesting to explore.
2.7 Considerations for Tisagenlecleucel Dosing Rationale
A recent abstract at ASCO® 2018, by Awasthi et al. (2018), analyzed data from pivotal phase II ELIANA [NCT02435849, n = 75], ENSIGN [NCT02228096, n = 29], and JULIET [NCT02445248, n = 99] trials to investigate tisagenlecleucel dose-related impact on efficacy, safety, and exposure. Unlike conventional drugs, the ultimate number of T cells in the patient is a function of in vivo expansion and thus is determined by various factors including patient characteristics (such as disease burden), manufacturing attributes, and indication. Final product attributes (transduction efficiency, percentage T cells, cell viability, total cell count), exposure (maximal in vivo expansion), efficacy, and safety were evaluated against dose. Dose and exposure were independent. Increased probability of any grade or grade III/IV CRS was associated with increase in dose in DLBCL; no impact was observed in B-ALL. Clinically meaningful responses were observed across the dose range. The proposed dose range, as CAR+ viable T cells, were based on totality of these analyses considering the benefit-risk ratio (B-ALL: body weight ≤ 50 kg, 0.2–5.0 × 106/kg, for weight > 50 kg, 0.1–2.5 × 108; DLBCL: 0.6–6.0 × 108).
2.8 US FDA Approval of Tocilizumab5 for Cytokine Release Syndrome
CRS is the most common risk associated with CAR T-cell therapies. On August 30, 2017, the US FDA also (along with tisagenlecleucel [see above]) approved tocilizumab for the treatment of patients 2 years of age or older with CRS that occurs with CAR T-cell therapy. In an analysis of data from clinical trials of CAR T cells, 69% of patients with severe or life-threatening CRS had resolution of CRS within 2 weeks following one or two doses of tocilizumab (see footnote 5).
2.9 Promise of Gene Therapy
Challenges and future directions in cell-based genetic therapies
• Careful surveillance to assess long-term outcomes is essential |
• Large multicenter prospective studies are needed to confirm the clinical efficacy and safety |
• Prospective data are needed on the influence of disease biology with CAR T-cell therapies |
• Disease- and patient-specific standardization and/or consensus on lymphodepleting conditioning regimens |
• Better understanding of therapy associated toxicities |
• Identification of pre-therapy biomarkers or models that may allow efficient prediction of clinical response to therapy |
• Optimization/standardization of the cell dose and formulation |
• Identification of new tumor-specific targets and subsequent development of dual- or even triple-targeting CAR T-cell products |
• Expansion of CAR T-cell therapy application to myeloid malignancies and solid tumors |
• Exploration of gene therapy earlier in the disease course may be worthwhile in selected group of patients |
• Better understanding of in vivo kinetics of gene therapy products with clinical responses and adverse effects is needed |
• Exploration of gene-based therapy in mitigating allogeneic hematopoietic cell transplant-associated graft-versus-host disease |
• Advancement of third party “allogeneic” CAR T cells clinical trials |
• Advancement and selection of best genome editing technologies |
• Selected patients might benefit with additional therapeutic modalities pre- or post-CAR T infusion (e.g., epigenetic modulation and PD-1 antibodies) |
• Hospital partnerships with biotechnology and pharmaceutical industries with expertise in manufacturing |
• Cell and gene therapy product must be delivered in a safe and timely manner |
• Standardization of generation and expansion of gene therapy products |
• Standardization of quality control is needed |
2.9.1 Cerebral Adrenoleukodystrophy
In X-linked adrenoleukodystrophy, mutations in ABCD1 lead to loss of function of the ALD protein. Cerebral adrenoleukodystrophy is characterized by demyelination and neurodegeneration. Disease progression, which leads to loss of neurologic function and death, can be halted only with allo-HCT (Eichler et al. 2017). A single group, open-label phase II/III (STARBEAM) study (Eichler et al. 2017) evaluated the safety and efficacy of autologous CD34+ cells transduced with the elivaldogene tavalentivec (Lenti-D) lentiviral vector for the treatment of early-stage childhood cerebral adrenoleukodystrophy. The inclusion criteria matched widely accepted eligibility criteria for allo-HCT in children with cerebral adrenoleukodystrophy. A total of 17 boys received Lenti-D gene therapy. At the time of the interim analysis, the median follow-up was 29.4 months (range, 21.6–42.0). All the patients had gene-marked cells after engraftment, with no evidence of preferential integration near known oncogenes or clonal outgrowth. Measurable ALD protein was observed in all the patients. No TRM or GvHD had been reported; 15 of the 17 patients (88%) were alive and free of major functional disability, with minimal clinical symptoms. One patient, who had had rapid neurologic deterioration, died due to disease progression. Another patient, who had evidence of disease progression on MRI, withdrew from the study to undergo allo-HCT and unfortunately died later from transplantation-related complications. These results suggest that autologous CD34+ cells transduced with Lenti-D are at least as effective as conventional allo-HCT for the treatment of cerebral adrenoleukodystrophy and may be safer.
2.9.2 Transfusion-Dependent β-Thalassemia: Results of HGB-204 and HGB-205 Studies
Donor availability and transplantation-related risks limit the broad use of allo-HCT in patients with transfusion-dependent β-thalassemia. After investigators previously established that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, they attempted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia (Thompson et al. 2018). In the two, phase I/II studies (Thompson et al. 2018), investigators obtained mobilized autologous CD34+ cells from 22 patients (age 12–35 years) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. At a median of 26 months (range, 15–42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β0/β0 genotype no longer required red blood cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In nine patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in three patients. Treatment-related AEs were typical of those associated with autologous hematopoietic cell transplantation. No clonal dominance related to vector integration was observed. The study (Thompson et al. 2018) concluded that gene therapy with autologous CD34+ cells transduced with the LentiGlobin BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious AEs related to the drug product.
2.10 Challenges
While exciting, it is important to note that most extant clinical data have short-term follow-up. Using CAR T cells for B-ALL as an example, the high response rates at early time-points translate to no higher than 50% disease-free survivals (DFS) beyond 6 months (Park et al. 2018; Maude et al. 2014). Leukemia relapses on these trials occurred either with loss of the CD19 antigen (a form of immunoediting) (Sotillo et al. 2015) or due to inadequate persistence of the CAR T cells (Park et al. 2018; Maude et al. 2014). Responses are lower in lymphomas than in ALL for reasons that remain incompletely elucidated, although complete responses in those lymphoma patients do appear to be durable. Thus, there is clearly room to improve (Table 2.1 and see text below). Widespread clinical deployment of these therapies has only just begun with the recent US FDA approval of tisagenlecleucel (see footnotes 1 and 3) and axicabtagene ciloleucel (see footnote 2) and will highlight logistical challenges associated with centralized manufacturing products from patients located at widely dispersed institutions. As noted above, the registration trials for both tisagenlecleucel (see footnotes 1 and 3) and axicabtagene ciloleucel (see footnote 2) showed that this is feasible, and we now await post-marketing experience. Further challenges to overcome are the frequent and at times severe toxicities that are beginning to seem to be a “class effect” of CAR T cells. CRS appears to be mediated by a cross talk between the infused T cells and the patient’s endogenous myeloid cells (Giavridis et al. 2018) yet whether CRS can be dissociated from the antitumor effect remains uncertain. Neurotoxicity, at least in patients with R/R ALL, seems to be related to disruption of the blood-brain barrier and correlates with high tumor burden, peak CAR T-cell expansion, and high levels of serum cytokines (Santomasso et al. 2018). Neurotoxicity is a particular challenge since specific therapy for this complication is lacking. Also noteworthy of reported trials is that patients have received T-cell products comprising often random compositions of CD4+ and CD8+ naive and memory T cells, meaning that each patient received a different therapeutic product. Such variation may have influenced the efficacy of T-cell therapy and complicates comparison of outcomes between different patients and across trials (Sommermeyer et al. 2016). Another barrier to the overall success of CAR T-cell strategies has been the exclusion of research participant enrollment (Singh et al. 2016). In addition, the hurdles for gene therapy for nonmalignant and other non-hematologic disorders remain, including understanding and preventing genotoxicity from integrating vectors or off-target genome editing, improving gene transfer or editing efficiency to levels necessary for treatment of many target diseases, preventing immune responses that limit in vivo administration of vectors or genome editing complexes (Dunbar et al. 2018; Khalil et al. 2016) (Table 2.1).
2.11 Future Directions
More effective and safer genetic engineering approaches have generated great enthusiasm in the field of hematologic malignancies (CAR T cells) and immunodeficiencies or hemoglobinopathies (hematopoietic stem cells gene engineering) (see subsequent chapters in the book). Other than the challenges outlined above and in Table 2.1 for the existing therapies, an enormous challenge remains in translating these therapies beyond the relatively few patients with lymphoid hematologic malignancies. In adults, acute myeloid leukemia is more common than ALL, and myelodysplastic syndromes remain incurable without allo-HCT. Yet due to the lack of a suitable myeloid antigen that is specific to cancer cells, approaches that can bring the power of CAR T-cell therapy to bear on myeloid malignancies remain an area of active investigation (Kim et al. 2018; Buddee et al. 2017) with a paucity of clinical results to date (NCT02159495 (Buddee et al. 2017) and NCT03190278). An even bigger problem and richer prize is the area of solid tumors, where CAR T cells have met with very little success to date. Here the issue is likely to be not only the lack of a suitable antigen but also the presence of a very immunosuppressive tumor microenvironment (TME) that is not conducive to T-cell activity. In the arena of solid tumors, the most convincing (albeit sparse) results have come from the infusion of ex vivo expanded tumor-infiltrating lymphocytes (TILs) into a select few patients with some very impressive results (Zacharakis et al. 2018; Tran et al. 2015, 2016, 2017). It is tempting to speculate that combining antigen-specific T cells with suitable inhibitors of negative signaling in the TME might yield more convincing responses. Finally, further work to streamline, harmonize, and simplify the manufacturing process is underway and could ultimately increase the feasibility and reduce the costs associated with genetically engineered cellular therapy, thereby moving it from a cottage industry into the mainstream.
Conflict of Interest
Syed A. Abutalib—None.
Saar I Gill—Research funding (Novartis); Equity (Carisma Therapeutics); Scientific Advisory Board (Carisma Therapeutics, Extellia Therapeutics).