1. Introduction

2. Different biological characteristics in pediatric and adults ALL patients

3. Evolution of ALL treatment applications

4. Immunotherapy for ALL

4.1. Bispecific antibodies (BsAbs)

BsAbs are antibodies engineered to contain two different fragment-binding antigens (Fabs) regions that allow for the concurrent targeting of two antigens. One of the main mechanisms of action of BsAbs is to recruit and activate effector cells (i.e., T cells) against target cells (i.e., tumor cells). These antibodies, unlike conventional ones, induce enhanced T-cell activation. BsAb-activated T cells exert their cytotoxic action on tumor cells by producing proteins such as perforin and granzymes. Perforin is responsible for pore formation in cell membranes, facilitating the entry of granzymes and thus, enabling their delivery into the cytosol to initiate apoptosis[62,63,64].

Blinatumomab is a bispecific Tcell-engaging (BiTE) antibody. BiTe antibodies lack the Fc fragment and are composed of the fusion of two different single-chain variable fragments (scFvs); one scFv binds the CD3 expressed on effector T cells and the other binds a tumor-associated antigen. Blinatumomab by simultaneously binding CD19 on B-ALL cells and CD3 on T cells, can mediate a direct cross-link between T cells and tumor cells[65,66], resulting in a targeted and highly effective tumor cell killing [67].

Figure 1. Blinatumomab immunotherapy for the treatment of CD19-positive Bcell precursor ALL. (A) Representative scheme depicting the structure of Blinatumomab. Blinatumomab is comprised of the fusion of the scFv of CD3 fused with a linker to the scFv of CD19. (B) Representative scheme depicting the mechanism of action of Blinatumomab. Blinatumomab can specifically bind both the CD3 expressed on T cells and the CD19 expressed on B-ALL cells, cross-linking the T cells and B-ALL cells and mediating cell lysis. Note: Figure created with BioRender.com.

Figure 1. Blinatumomab immunotherapy for the treatment of CD19-positive Bcell precursor ALL. (A) Representative scheme depicting the structure of Blinatumomab. Blinatumomab is comprised of the fusion of the scFv of CD3 fused with a linker to the scFv of CD19. (B) Representative scheme depicting the mechanism of action of Blinatumomab. Blinatumomab can specifically bind both the CD3 expressed on T cells and the CD19 expressed on B-ALL cells, cross-linking the T cells and B-ALL cells and mediating cell lysis. Note: Figure created with BioRender.com.

It is the first FDA-approved BiTE antibody to treat minimal residual disease (MRD)-positive BCP-ALL, as well as for relapsed or refractory (R/R) ALL, both in adult [68,69] and pediatric patients[70]. According to European Medicines Agency (EMA), the use of blinatumomab in the pediatric population is limited to children aged one or older with Philadelphia chromosome-negative CD19 positive Bcell precursor ALL (CD19+R/R Ph-negative BCP-ALL), which is refractory or in relapse after receiving at least two prior therapies or in relapse after receiving prior HSCT[71]. Cytokine release syndrome (CRS) and neurotoxicity are reported as the main adverse events, most of which can be rapidly resolved.

4.3. Chimeric antigen receptor (CAR)-engineered immune cell therapy in ALL

In this section, we will review one of the most promising immunotherapy approaches for ALL, consisting of the genetic modification of immune cells such as T-cells and also NK cells with chimeric antigen receptors (CARs). It’s known that the immune system plays a crucial role in tumor growth control. The tumor, however, may escape detection by the immune system, and its growth and progression are controlled by TME. Hypoxia, also as a consequence of ischemia or nutrient deprivation are only some of the ways used by TME to destabilize immune cells. Hypoxia can shape the type and function of immune cell infiltration in the TME by polarizing tumor-associated macrophages (TMA) toward anti-inflammatory M2 macrophages and cytokines[119,120,121,122]. Furthermore, immune cell dysfunction is mediated by a series of factors including the changes in signal transduction molecules, loss of TSA, stimulation of CTLA4 on T cells, and secretion of some soluble molecules by tumor or non-tumor cells in the TME, other than by the presence of some immunosuppressive cells in TME[123,124]. In this context, the engineering of CART cells has become the new frontier of immunotherapy in the treatment of hematological malignancies, even if it has important adverse events limiting its success. CRS and neurotoxicity together to on-target off-tumor effects and GVHD are only some of the restrictions linked to a broader application of CART cell therapy in hematological disease treatment. To overcome these limitations, other immune effector cells that may be modified with CARs and used in immunotherapy are being studied. The scientific focus has recently shifted to NK cells, whose particular molecular peculiarities make them suitable for an “off-the-shelf” allogeneic therapy. First, it’s possible to produce big NK cells quantities from several sources and this, together with a minimal risk of toxicity or GVHD permitted by the HLA-I dominant-negative regulatory function on NK killing activity, and a minor cost of production makes CARNK cell therapy the future of immunotherapy for leukemia.

4.3.1. CART Cells

CART cell therapy is based on the genetic engineering of a patient’s T cells to induce the expression of a chimeric receptor able to recognize a marker expressed on tumor cells leading to cancer cell elimination. T cells are sampled from the patient’s peripheral blood and transduced with viral vectors encoding the desired genes. Genetically engineered cells are then expanded in vitro before re-infusion into the patient’s blood (Figure 4).

Currently, CART cells can be categorized into four generations based on the organization of their intracellular signaling domain, with fifth-generation CARs similar to the second-generation, but with an intracellular domain of a cytokine receptor[125,126,127,128,129,130].

CD19 is an ideal target antigen for CART cell therapy and encouraging results have been reported in the treatment of several types of B cell malignancies[131]. In 2013, for the first time, CD19-directed CART (CART 19) cells have been successfully used in two children with chemotherapy-resistant ALL, and, despite the presence of severe CRS and B-aplasia, CR was achieved in both patients[132]. Since that, several investigations have been carried out to better understand the CR rate and the durability of the CART cell therapy effect, and, early reports demonstrated the potential benefits of CAR T cells in R/R B-ALL[133,134,135,136,137,138].

In 2018, FDA approved the anti-CD19 CART cell therapy tisagenlecleucel (CTL019) for R/R B-ALL based on the results of the ELIANA multicenter study (ClinicalTrials.gov number, NCT02435849) that showed high response rates in patients up to 25 years of age. Although transient high-grade toxic effects occurred, an overall remission rate of 81% among 75 patients at 3 months of follow-up after a single infusion of tisagenlecleucel has been reported[133].

In the same year, Park et al. used a CD19 CART construct with a CD28 costimulatory domain (19-28z) in a phase 1 trial on 53 adults with relapsed B-cell ALL. They hypothesized that the safety and long-term efficacy of 19-28z CART cells may be associated with the clinical characteristics of the patients, disease characteristics, the treatment regimen, and the kinetics of T-cell expansion. They reported that 14 out of 53 patients developed severe CRS and 1 patient died. CR was achieved in 83% of the patients and MRD response was observed in 67%. The median OS was 12.9 months. 19-28z CART cell therapy (median follow-up of 29 months) showed a favorable long-term remission rate in patients with a low disease burden, who had significantly longer event-free survival and OS with a markedly lower incidence of toxic effects than did those with a high disease burden[135].

KTE-X19, another anti-CD19 CART cell therapy, already approved for non-Hodgkin lymphoma, has also been studied for the treatment of B-ALL. Data from the ZUMA-3 trial, which has been conducted on adult patients with R/R B-ALL, showed a high response rate and tolerable safety of KTE-X19. Fifty-four patients were enrolled in phase 2 of the trial and 45 of them received a single infusion of the CD19-directed product (2×10⁶, 1×10⁶, or 0.5×10⁶ cells per kg) after lymphodepleting chemotherapy. Severe CRS and neurotoxicity, which occurred respectively in 31% and 38% of the patients, were successfully managed. CR was achieved in 52% of patients within 3 months[139]. Furthermore, at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting, Shah, et al. presented the results of the phase 2 portion of this trial reporting that the CR/CRi rate was 71%. After a median follow-up of 16.4 months, KTE-X19 showed compelling clinical benefit in heavily pretreated adults with R/R B-ALL, with the median OS not yet reached for responding pts and a manageable safety profile[140]. Finally, in October 2021, KTE-X19 was approved as the first CART cell therapy for adults with R/R B-ALL.

Interestingly, CART cells can migrate to CNS or testes and thus, can be considered a good therapeutic choice also for the treatment of CNS-relapsed leukemia[141,142,143]. In 2015, Rheingold et al. demonstrated that CTL019 was detectable in cerebrospinal fluid in 46 out of 47 treated patients with B-ALL, indicating the ability of this therapy to cross the blood-brain barrier [144]. To date, only a few results are available on the efficacy of CART cell therapy in patients with R/R B ALL and active CNS disease [136,145,146]. However, data from the CHP959 trial (NC01626495), carried out on 65 patients with CNS involvement showed no significant differences in relapse-free survival or neurological toxicities between patients with active CNS disease and those without it, before CD19 CART cell infusion[147]. Other studies confirmed the efficacy of this treatment in patients with multiply relapsed or refractory extramedullary leukemia [148,149].

The value of CART cells is undeniable in the treatment of B-ALL, but it is necessary to understand how to minimize toxicities such as CRS, immune effector cell associated neurotoxicity syndrome (ICANS), and B-cell aplasia related to it, particularly in adult patients. CRS is a systemic inflammatory response that is often associated with CART cell therapy within 1-4 days after the infusion and can progress to multiple organ dysfunction. Learning how to recognize early CRS is a fundamental step to treating it promptly and preserving life-threatening consequences. Of note, higher grade CRS has been associated with higher disease burden and may be effectively treated with the anti-interleukin-6 receptor antibody tocilizumab that, however, could limit the efficacy of the immunotherapy [150,151]. In addition, a relationship between CART dose and CRS occurrence has been highlighted[152]. Therefore, the adoption of a fractionated dosing scheme might be a good strategy to retain high response rates with acceptable tolerability. Meaningful advancement was shown by Frey’s group which demonstrated that fractionation of CTL019 dosing treatment can help manage CRS toxicity and maintain efficacy in adults with R/R ALL [153]. ICANS is also associated with CART cell therapies and it seems due to both activated CART and endogenous T lymphocytes and the cytokines secreted by them [154,155,156]. It can occur in association with or following CRS and its management continues to evolve and constitutes an area of ongoing research. In addition, B cell aplasia represents another CART cell-related toxicity linked to CD19 CART cell therapy for B-ALL[157]. Hypogammaglobulinemia and agammaglobulinemia caused by Bcell aplasia expose patients to an increased risk of infections that needs to be promptly managed to avoid lethal consequences[157,158]. To this aim, immunoglobulin replacement may help to prevent serious bacterial infections[133,159,160,161,162]. It has been demonstrated that increasing serum IgG levels may result in protection against infections [157]. Moreover, antimicrobial and antifungal prophylaxis is also recommended in the prevention of infections in patients treated with CD19-redirected CART cell therapy [163,164,165]. In case of viral infections such as herpes simplex virus and varicella zoster virus reactivation, following CD19 redirected CART therapy, antiviral prophylaxis should be considered. Already in the past, researchers were interested in studying the possible impacts of immunotherapy in leukemic patients with viral infections such as HIV, hepatitis B, and C. Until the past few years, in the presence of viral infections, patients were not considered for immunotherapy treatment that could worsen the infection.

However, during the COVID-19 pandemic, studies on the interaction between the immune system and acute respiratory syndrome coronavirus 2 (Sars-Cov-2) indicated that the coronavirus can promote PD-L1 expression, towards which several immunotherapy drugs are directed. Therefore, in the case of coronavirus infection, in the early phases, an immunotherapy regimen could have positive effects in counteracting the virus, by stimulating the patient’s immune system against it. Instead, in severe Sars-Cov-2, the use of immunotherapies could represent a risk for the inflammatory storm associated with a hyperactive inflammatory response. Recently, a prolonged severe Sars-Cov-2 infection in a BCMA-redirected CART cell therapy recipient was described. Despite convalescent plasma therapy and antiviral prophylaxis with the agent remdesivir, the patient experienced a massive lung infection and died from infection-related complications[166].

4.3.2. CARNK cell therapy

As depicted in Figure 5, NK cell activity is controlled by multiple inhibitory or stimulating receptor-ligand interactions depending on a health condition or disease [167].

NK cells are heterogenous and distinct cell subsets mediating specialized functions. The tissue of origin of NK cells is the bone marrow in which IL15 and a to lesser extent IL2 play a pivotal role in NK cell development and differentiation[168,169]. Among NK cells, two cell subsets emerge in terms of cell function. The first subset is composed of the classic cytotoxic cells while the second subset is composed of NK cells with regulatory functions. Both NK cell subsets are defined according to the intensity of cell surface expression of CD56 and CD16. The previous includes CD56^lowCD16^highcells while the latter is characterized by CD56^highCD16^low/negcells. The CD56^lowCD16^high are professional killer cells. NK cell cytotoxicity is regulated by a balance between activatory and inhibitory molecules termed natural cytotoxic receptors and killer inhibitory receptors (KIRs) respectively (missing-cell hypothesis); Figure 5[170]. The role of NK cells in the host defense against solid tumors is unclear. However, there is evidence that NK cells may play a minimal direct role in counteracting epithelial cancers, but, they can cooperate with T cells in controlling tumor progression. For example, NK cells are barely found in the TME, and even if they are found may not be associated with improved survival[171,172,173]. However, pre-clinical and clinical studies have shown that NK cells play a pivotal role in the immune response against leukaemia in allogeneic, HLA-matched, and unmatched settings. Unlike T cells, they do not mediate GVHD. As a consequence, NK cells are interesting effector cells for cell-based immunotherapy for leaukemias[174,175].

NK cells can be obtained from several sources including donor or autologous peripheral blood mononuclear cells (PBMC), umbilical cord (UCB), cell lines (NK-92), pluripotent stem cells (PSC) from human embryonic stem cells (hESC), and induced pluripotent stem cells (iPSC). All these sources of NK cells can, subsequently, be engineered with a CAR, expanded, and infused into the patient.

Figure 6. Novel CARNK cell therapy.Representative scheme depicting the process of CARNK cell generation for clinical use. Various cellularsources are utilized for the isolation or differentiation of NK cells.The NK cells are then engineered to express a CAR on their surface and expanded in culture.Following ex vivoexpansion, the CARNK cells are infused into the patient and are re-directed to target and destroy cancer cells. Note: Figure created with BioRender.com.

Figure 6. Novel CARNK cell therapy.Representative scheme depicting the process of CARNK cell generation for clinical use. Various cellularsources are utilized for the isolation or differentiation of NK cells.The NK cells are then engineered to express a CAR on their surface and expanded in culture.Following ex vivoexpansion, the CARNK cells are infused into the patient and are re-directed to target and destroy cancer cells. Note: Figure created with BioRender.com.

Analyzing and comparing the efficacy of methods for NK cell engineering, it has been shown that NK cells can be quickly isolated from peripheral blood (PB) however, they are difficult to engineer due to low transduction efficiency combined with poor expansion. Instead, NK-92 cells demonstrate a strong anti-tumor activity [176] that makes them a good option for engineering, even if they need to be irradiated before use to prevent lethal effects. To overcome the limitations of long-term storage decreasing the cytotoxic capabilities, a good choiceis given by UCB-derived NK cells. Indeed, these cells may undergo cryopreservation with minimal alterations, and despite their relatively immature nature, exhibit high proliferative capabilities and work effectively for in vivo studies compared to PB-derived NK cells[176]. Also manufacturing iPSC-NK cells may be considered a good alternative. IPSC-NK cells are quick to obtain, safe, and show high cytotoxic activity against tumor cells. To further improve the efficacy of CARNK cells, several gene editing strategies to enhance their potential, their persistence, and homing are being studied [177].

NK cell-mediated immunotherapy is based on increased NK cell activation via blocking inhibitory interactions, expanding NK cell populations, and improving overall function. Although it is still in the experimental phase, its potential is amply suggested by longer survival and reduced relapse together with fewer adverse effects than CART cell therapies[178].

Initial studies on CARNK cells have been initiated by CART cell constructs since NK cells and T cells share some costimulator domains such as 4-1BB. However, other co-stimulatory domains, more specific for NK cell signaling, are being investigated. In particular, NKG2D and CD244 (2B4) are the two costimulatory molecules through which, NK cells raise their cytotoxic capability and cytokine production [179]. Early results from ongoing clinical trials are encouraging and demonstrate that NK cells provide a safer and more advantageous CAR-engineering platform than that T cells[180]. This permits us to hypothesize that a large number of patients can be treated on demand with this new immunotherapy. However, to date, only a few clinical studies of CARNK cell immunotherapy for ALL patients are going on. This may be partially due to the modest outcomes obtained from the use of first-generation CARNK cells [181]. Among the most promising clinical trials, there is NCT05020678, a single-arm, open-label, multicenter, phase 1 study that is ongoing to evaluate the safety and tolerability of an experimental intravenous allogeneic CARNK cell targeting CD19 (NKX019) in adult patients (n=60) with relapsed/refractory NHL, CLL or B-ALL. NCT05563545, a single-arm clinical study, is instead recruiting cases with recurrent or refractory CD19 positive ALL to evaluate the safety, dose, tolerance, and pharmacokinetic characteristics of CARNK-CD19 (SNC103) and also define the effectiveness, the immunogenicity of the product, and the correlation between the changes of cytokines after infusion and CRS, ICANS. Furthermore, in NCT04796688, patients with CD19+ R/R ALL are being recruited to be treated with fludarabine + cyclophosphamide + CARNK-CD19 cells and evaluate the safety and efficacy of universal CAR-modified AT19 cells. Instead, in NCT04796675, NK cells derived from healthy donor cord blood (CB) have been engineered with an anti-CD19 CAR to test their safety and efficacy in patients with CD19+ Bcell malignancies. Also in the active, but still not recruiting NCT03056339 clinical study, CB-derived NK cells are being used. The purpose of the study is to learn if iC9/CAR.19/IL15-transduced CB-NK cells infusion, after fludarabine and cyclophosphamide or mesna chemotherapy, improves the disease in patients with R/R B-cell leukemia. Another goal of the study is to find the highest tolerable dose of CARNK cells to give to patients and evaluate the safety of this treatment. Among the several NK lines, the NK-92 cell line has been successfully modified to express CARs recognizing antigens expressed on tumor cells and may be considered an ideal source for cell-based immunotherapy. Previous phase 1 clinical study has demonstrated that NK-92 cells can be irradiated at very high doses with minimal toxicity in patients with refractory hematologic tumors, who had relapsed after autologous hematopoietic cell transplantation [182]. The clinical trial NCT02892695 started in 2016, is one of the first clinical trials with engineered NK-92 cells for CAR therapy. Ten patients with leukemia (including ALL) or lymphoma have been enrolled to evaluate the safety and optimal dose of CARNK PCAR-119 used as bridge immunotherapy before receiving stem cell transplantation. In the ongoing NCT02727803 phase II study, CAR-engineered NK-92 cells are used in patients (estimated enrollment of 100 patients with myelodysplastic syndrome, leukemia, lymphoma, or multiple myeloma) that have received cord blood transplantation.

The primary objective of the study is to define the progression-free survival (PFS) time and then evaluate OS time for treatment-related mortality (TRM) and adverse events (GVHD/infection). In addition to CD19, another promising target for CARNK cell therapy is CD7. In NCT02742727, the NK-92 cell line has been engineered to express an anti-CD7 attached to TCRzeta, CD28, and 4-1BB signaling domains and to be infused in patients with CD7-positive R/R leukemia and lymphoma to evaluate its safety and effectiveness. The NCT02890758 clinical trial is underway to investigate the number of NK cells from non-HLA matched donors (this kind of infusion is still experimental and not approved by the FDA) that can be safely infused into patients with hematologic tumors. After receiving the NK cells, patients may also be given ALT803, a drug that keeps NK cells alive, promotes their expansion, and supports their cancer-fighting characteristics. Furthermore, to enhance the therapeutic utility of NK-92 cells for the treatment of B-ALL, Oelsner et al. engineered NK-92 cells with an FMS-like tyrosine kinase 3 (FLT3)-specific CAR containing a composite CD28-CD3ζ signaling domain. Their results suggest that FLT3-specific CAR NK cells exhibit high and selective cytotoxic activity against established and primary B-ALL cells in vitro and, in a NOD/SCID IL2Rγ-null mouse xenograft model of B-ALL, a remarkable inhibition of disease progression is observed thus demonstrating high antileukemic activity in vivo [183].

5. New treatments under investigation

6. Conclusions

References

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