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Published in final edited form as: Biol Blood Marrow Transplant. 2015 Oct 17;22(1):17–22. doi: 10.1016/j.bbmt.2015.10.014

Fast Cars and No Brakes: Autologous Stem Cell Transplantation as a Platform for Novel Immunotherapies

Miguel-Angel Perales 1,2, Craig S Sauter 1,2, Philippe Armand 3
PMCID: PMC4706480  NIHMSID: NIHMS731512  PMID: 26485445

Abstract

Autologous stem cell transplantation (ASCT) is indicated in a number of hematologic malignancies, including multiple myeloma, non-Hodgkin lymphoma and Hodgkin lymphoma. Relapse however remains one of the main causes of post-ASCT failures, and several strategies are being investigated to decrease the risk of relapse of progression. Recent advances in the treatment of hematological malignancies have included adoptive transfer of genetically modified T cells that express chimeric antigen receptors or T cell receptors, as well the use of checkpoint inhibitors. Early clinical results in non-transplant patients have been very promising. This review will focus on the use of gene-modified T cells and checkpoint inhibitors in stem cell transplantation.

Introduction

Autologous stem cell transplantation (ASCT) is indicated in a number of hematologic malignancies, including multiple myeloma (MM), non-Hodgkin lymphoma (NHL) and Hodgkin lymphoma (HL) (1-6). Relapse, however, remains one of the main causes of post-ASCT failure, and several strategies are being investigated to decrease the risk of relapse of progression. Furthermore, some patients may not be candidates for ASCT due to inadequate response to salvage therapy. Although the ongoing development of novel targeted therapies impacts the actual indications of ASCT, there remains a significant unmet need for novel approaches to improve disease control in the setting of ASCT. The benefits of increasing regimen intensity, for example, need to be weighed against the risk of increased toxicity and may differ for different histologies (7). The use of post-transplant maintenance or consolidation has been validated in several indications and has been previously reviewed in this journal (8). More recently, significant advances in the treatment of hematological malignancies have been made in the field of immunotherapy (9-14). This includes adoptive transfer of genetically modified T cells that express chimeric antigen receptors (CAR) or T cell receptors (TCR) (9-11), as well as the growing use of antibody-based approaches with checkpoint inhibitors (12, 13). In this review, we will on these approaches in the context of hematopoietic stem cell transplantation (HCT).

Paving the Road for CARs: CAR Modified T Cells Directed Against CD19 Following High-Dose Therapy and Autologous Transplantation

The cluster of differentiation antigen 19 (CD19) is a 95 kD transmembrane glycoprotein ubiquitously expressed on B cells from pro-B to mature B cell phenotypes, including all B-cell NHL (B-NHL)/chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and B cell acute lymphoblastic leukemia (B-ALL). CD19 is not expressed on other hematopoietic, or organ, cell populations. While targeting CD19 can hypothetically result in B cell aplasia, the clinical experience with the anti-CD20 monoclonal antibody rituximab has shown that this does not result in severe consequences. Thus, CD19 serves as an acceptable tumor antigen to target for cellular therapy. Genetically engineered recombinant T cell receptors directed against a specific tumor antigen (chimeric antigen receptors, CARs) can recognize and lyse tumor targets. While most of the clinical experience of targeting CD19 with CAR modified T cells (19-CAR-T) to date has been reported in patients with acute lymphoblastic leukemia (15-20), the present section will focus on the use of 19-CAR-T for B-NHL, excluding CLL/SLL.

The initial CAR constructs consisted of an antigen recognizing single chain variable fragment (scFv) extracellular domain from an antibody with a transmembrane link to a functional CD3ζ intracellular signaling domain (21). While this initial design demonstrated T cell effector function, proliferation and expansion was not achieved until second-signal transmembrane costimulatory domains were constructed into the later generation design (22). This translated into improved anti-tumor efficacy in early animal models compared to first generation constructs (23). The clinical experience of 19-CAR-T for B-NHL reviewed in this manuscript will largely focus on second-generation 19-CAR-T constructs with TCR/CD3 signal 1 coupled to signal 2 with either CD28, 4-1BB or OX40.

Clinical Studies: 19-CAR-T for B-NHL

The first clinical experience in 19-CAR-T for patients with follicular lymphoma (FL, n=2) and diffuse large B cell lymphoma (DLBCL, n=2) was from the City of Hope with a first-generation construct (24). Both DLBCL patients received 19-CAR-T one month following high-dose therapy and autologous stem cell transplantation and 1 of 2 remained progression-free at the time of publication. The two patients with FL progressed following therapy. Significant toxicity was not observed and 19-CAR-T failed to persist with only 1 of 4 patients demonstrating peripheral 19-CAR-T persistence at one week with this first generation construct, despite IL-2 being exogenously administered in the 2 FL patients.

The first case-report of a second generation 19-CAR-T incorporating a CD28 co-stimulatory domain was published in a patient with FL treated along with exogenous IL-2 at the NCI (25). The patient experienced a partial remission (PR) lasting approximately 10 months and 19-CAR-T persistence for > 6 months. More recently, the NCI group has updated its prospective experience of 19-CAR-T with CD28 co-stimulation for refractory B-NHL preceded by lympho-depleting chemotherapy consisting of cyclophosphamide 60-120 mg/kg and fludarabine at a total dose of 125 mg/m2 (26). Six of 7 patients with DLBCL responded with either a complete (CR) or partial remission and all 6 patients with indolent B-NHL responded (PR or CR). The longest responses were 1 and 2 years of DLBCL and indolent B-NHL respectively. The 19-CAR-T expansion peaked from 7-17 days. The investigators lowered the dose of 19-CAR-T from 5 × 106/kg to 1 × 106/kg due to toxicity, most notably cytokine-release syndrome (CRS). Thirteen of 15 patients experienced ≥ grade 3 toxicity predominately with manifestations of CRS. In a sequential study presented at the American Society of Hematology (ASH) meeting in 2014, the NCI investigators studied lower dose chemotherapy (cyclophosphamide 900 mg/m2 and fludarabine 90 mg/m2), and noted less toxicity related to severe CRS with too few patients to assess impact on disease efficacy (27).

The group from the University of Pennsylvania recently presented interim results of their phase IIa study treating chemorefractory FL, mantle cell lymphoma (MCL) and DLBCL patients with 19-CAR-T at the 2015 American Society of Clinical Oncology (ASCO) meeting (28). The construct of their second-generation 19-CAR-T incorporates a 4-1BB co-stimulatory transmembrane domain. Patients were treated with variable lymphodepleting chemotherapy prior to administration of 19-CAR-T on study. Of 12 evaluable patients treated with DLBCL, 2 patients had a CR and 4 had a PR to 19-CAR-T for an overall response rate (ORR) of 50%. The longest responder is in continued remission > 1 year post-19-CAR-T. All 7 patients with FL responded with the longest remission being > 1 year post-treatment while 1 of 2 patients with MCL experienced a response with < 2 months of follow-up. The investigators observed 12 non-hematologic toxic events ≥ grade 3 with 4 of these events related to CRS or neurotoxicity. The Fred Hutchinson Cancer Research Center group recently presented an update at ASCO 2015 of 19-CAR-T with 4-1BB co-stimulation for refractory B-cell malignancies (29). Their study is unique in that the 19-CAR-T are composed of a fixed 1:1 ratio of CD8+ T central memory cells to CD4+ T cells based on encouraging pre-clinical data (30). Seven of 13 B-NHL patients responded (CR n=1, PR n=6) with no episodes of severe CRS observed. Clinical responses correlated to peak and persistence of 19-CAR-T in this interim analysis.

Lastly, investigators from Memorial Sloan Kettering Cancer Center (MSKCC) are currently testing 19-CAR-T in consolidation for high-risk relapsed/refractory DLBCL/aggressive histology B-NHL in partial chemosensitive remission following a HDT-ASCT (NCT01840566) (31). The rationale for this study is administering the cellular immune therapy in a lymphoablative setting immediately following HDT-ASCT (2 and 3 days following stem cell re-infusion) for potential optimization of 19-CAR-T expansion and efficacy. The 19-CAR-T utilized by this group includes a CD28 co-stimulatory molecule. An interim update presented at the 2015 ASCO meeting revealed 4 of 10 evaluable patients in continuous remission at a median of 14 months, and up to nearly two years in 2 patients, following study treatment (31). While this group has previously reported peak C-reactive protein to correlate with CRS, this correlation was not observed in the first 11 patients. All but one patient developed fevers, as expected, in neutropenic nadir. The most common ≥ grade 3 toxicity was reversible neurotoxicity in 7/11 patients, which the investigators attributed to CRS. The study is ongoing and expanding at the first dose level of 5 × 106/kg 19-CAR-T.

Limitations and future directions

Despite encouraging data, 19-CAR-T therapy for B-NHL has not matched the extremely impressive activity of this modality in B-ALL wherein the vast majority of patients achieve CR (15, 18). Whether this is due to micro-environmental phenotypic differences (marrow versus nodal based disease) or other factors between B-ALL and B-NHL remains highly speculative. As outlined above, the two major toxicities of 19-CAR-T therapy include CRS and neurologic manifestations including, but not limited to seizures, seizure-like activity, focal motor deficits, aphasia and global encephalopathy (32). Strategies being developed to circumnavigate, or treat, these toxicities include the use of anti-IL-6 receptor blockade (15), and engineering suicide genetic elements to ‘turn-off’ the activated cellular product when toxicity is observed (33). The goal will be to abrogate toxicity without ablation of the cellular therapy, for which corticosteroids currently serve in severe and recalcitrant toxicity. Future investigation toward improvement in 19-CAR-T efficacy for B-NHL may involve further co-stimulatory elements and/or lymphoproliferative cytokine genes engineered into the 19-CAR-T product (34). Additionally, combinatorial antigen specificity warrants clinical investigation (35). Lastly, the potential for immune-checkpoint blockade in combination with 19-CAR-T has yet to be investigated and has rationale, especially considering phenotypic changes once the cellular product is activated (36).

Checkpoint Blockade in Transplantation

Immune checkpoints are signaling pathways used to modulate the host's immune response, and are involved in the normal regulation of immunity and establishment of tolerance. However, those pathways can be usurped by malignant cells to evade immune surveillance. The recognition of this phenomenon has allowed the development of checkpoint blockade, a strategy through which key checkpoint pathways are interrupted or stimulated in an attempt to effect therapeutic anti-tumor activity. At present, the two principal checkpoint pathways being targeted in oncology are the cytotoxic T-lymphocyte associated protein 4 (CTLA-4) and programmed-death 1 (PD-1) pathways. The biology of those pathways has been reviewed elsewhere (37-39). Through monoclonal antibodies (mAbs) directed against the receptors or ligands involved in those pathways, the tumor-induced down-regulation of T cell function can be reversed, and clinically effective anti-tumor activity can ensue.

Checkpoint blockade therapy (CBT) has already yielded paradigm-changing results in solid tumor treatments, especially in melanoma, lung cancer, and renal cell cancer, among others (37-44). Hematologic malignancies are also a very tempting target for CBT (12, 13). Indeed, those tumors are known to be curable in a subset of patients through allogeneic hematopoietic stem cell transplantation (alloHCT), which relies principally on immune-based tumor eradication. Early clinical trials of PD-1 blockade using the mAb pidilizumab suggested activity in lymphoid malignancies (45), further supported by the encouraging responses in a phase 2 trial of rituximab + pidilizumab in follicular lymphoma (46). A phase 1 study of the anti-CTLA-4 mAb ipilimumab in lymphoma also demonstrated that this agent could yield durable responses (47). More recently, larger phase 1 studies using two different PD-1 mAbs, nivolumab and pembrolizumab, have tested this strategy across several hematologic malignancies. The first study tested the safety and efficacy of nivolumab in patients with relapsed or refractory (R/R) MM, NHL, and classical HL. The second study (KEYNOTE-013) tested pembrolizumab in R/R myelodysplastic syndromes (MDS), MM, NHL and HL. Preliminary results of both studies have been reported (48, 49). In both trials, HL was included based on the frequent amplification of genetic material at 9p24, which results in the over-expression of the PD-1 ligands, PD-L1 and PD-L2 (50). This and other mechanisms result in a very high frequency of PD-L1/PD-L2 expression on the surface of the HL tumor cell surface (51), suggesting that HL is a uniquely vulnerable target for PD-1 blockade. The clinical results to date have validated their scientific underpinning, with overall response rates of 87% with nivolumab and 65% with pembrolizumab. Moreover, the responses appear durable, with a median duration not reached in the nivolumab study after 86 weeks of follow-up. The activity of nivolumab in other hematologic malignancies was quite variable, with response rates of 36-40% noted in follicular lymphoma, DLBCL, and T-cell lymphoma, in contrast to MM where there were no objective responses (52, 53). Results of pembrolizumab outside of HL have not yet been reported.

CBT in Autologous Stem Cell Transplantation

There is now a tremendous amount of interest and activity around CBT in hematologic malignancies; many of the trials in progress or in planning target patients with R/R disease. Yet other settings could possibly lend themselves better to the deployment of this strategy. One such setting is the post-ASCT period. It is characterized by a minimal residual disease and by a remodeling immune system; moreover, in the first six months or so after transplantation, there is a relative dominance of the lymphocyte subsets that are the likely targets of PD-1 blockade (54, 55). CBT post-ASCT may therefore have benefits beyond what it can achieve in R/R disease. This hypothesis was first tested in an international phase 2 trial of the anti-PD-1 antibody pidilizumab, administered to patients with DLBCL after ASCT (56). In this trial, patients received 3 doses of pidilizumab. The 18-month progression-free survival (PFS) among the 66 eligible patients was 72%, which met the study's primary endpoint. Notably, the 18-month PFS was 70% among the 24 patients who had a positive PET scan after pre-ASCT salvage therapy, which is now known to be a high-risk feature in patients undergoing ASCT (57, 58). These results compared favorably to the 52% PFS in a historical control population. Also encouraging was the response rate of 51% to pidilizumab in patients who had measurable disease after ASCT (with a 34% CR rate). This study, while not definitive based on its single-arm phase 2 design, does lend support to the idea that PD-1 blockade post-ASCT may have useful activity. Studies are currently underway testing post-ASCT PD-1 blockade in patients with HL or DLBCL (NCT02362997) and MM (NCT02331368).

CBT after Allogeneic Stem Cell Transplantation

In the case of alloHCT, the goal is to engage a grafted immune system to cure R/R hematologic malignanciess, but the treatment is associated both with a high relapse risk and with significant toxicity. Immune checkpoint pathways may be used as a mechanism of tumor survival post transplantation (59, 60). Therefore, the use of CBT after alloHCT could in theory potentiate the salutary graft-versus-tumor effect and decrease the risk of relapse. If so, CBT could be used in patients with post-alloHCT relapse or in those at particular high risk of post-transplantation relapse. The major concern with the use of CBT after alloHCT is the possibility that it could unleash severe graft-versus-host disease (GVHD), which has tempered the enthusiasm for conducting CBT studies in allografted patients. Nonetheless, two clinical trials have already been performed with CTLA-4 blockade and provide a useful foundation on which future trials may be built. The first was a phase 1 study of ipilimumab administered in a single dose to patients with relapsed hematologic malignancies after alloHCT (61). Most importantly, this treatment appeared safe, which is as mentioned above a critical concern for post-alloHCT CBT. Specifically, with 29 patients treated up to a dose of 3.0 mg/kg, there was no severe GVHD, no dose-limiting toxicity, and only 3 related grade 3 or 4 events. Not only was the safety profile favorable, but there was also some evidence of efficacy: 2 patients with HL achieved a complete remission (CR), and 1 patient with mantle cell lymphoma achieved a partial remission (PR). Building on those results, a phase 1b trial (NCT01822509) is currently underway testing repeated doses of ipilimumab in this setting (4 doses every 3 weeks, followed by maintenance treatment every 12 weeks). Preliminary results have been reported (62). At the time of last analysis, 28 patients had been treated, 26 of whom were evaluable for response. Among those, 27% had an objective response. Notably, there were 4 CRs among 12 patients with relapsed AML. All responses occurred at the 10mg/kg dose level. However, this treatment was associated with non-negligible toxicity, including grade 3 GVHD and 2 severe immune-related adverse events. Overall, these preliminary results suggest that CBT may be feasible and effective after allogeneic transplant, although additional work is needed to clarify the optimal dose and schedule. Planned studies will also examine the safety and efficacy of PD-1 blockade in this setting. In general, PD-1 blockade has been more extensively tested in hematologic malignancies than CTLA-4 blockade, following the results in solid tumors where PD-1 blockade is associated with a better ratio of efficacy to toxicity. However, the post-alloHCT setting could be different, as pre-clinical studies in murine models have raised the possibility that blocking PD-L1 could result in significant GVHD (63).

Also relevant to alloHCT is the question of whether PD-1 blockade is safe before transplantation. Indeed, because anti-PD1 mAbs appear to have a long tissue half-life, they may continue to exert an effect in patients who proceed to alloHCT after PD-1 blockade, which could theoretically improve the efficacy of HCT (through enhanced GVT) or increase its toxicity (by increasing the incidence or severity of GVHD and other immune-related toxicities). It will be very important to carefully describe the outcome of those patients as we accumulate experience in this domain.

Future Directions

Checkpoint blockade has already transformed the treatment of several solid tumors, and may do the same in certain hematologic malignancies such as Hodgkin lymphoma. Much remains to be elucidated about which tumors to target, which checkpoint pathways to disrupt, which other types of treatment to best combine with CBT, and in which setting to most safely and effectively use this modality. Stem cell transplantation, both autologous and allogeneic, may provide a fertile ground for CBT, as in both cases the immune landscape may be particularly favorable for this type of intervention. Ongoing and future studies will shed further light on this question, in the ultimate hope of increasing the cure rates for patients with hematologic neoplasms.

Adoptive cell therapy and checkpoint inhibitors in multiple myeloma

ASCT is considered a standard treatment for patients with MM (2, 6). Although clinical outcomes have improved significantly with ASCT as well as the introduction of immunomodulatory drugs (IMiDs: thalidomide, lenalidomide and pomalidomide) and proteasome inhibitors (bortezomib and carfilzomib), most patients are not cured. As noted above, the role of post-transplant maintenance in MM has been reviewed previously (8). In this section, we will review approaches to target tumor antigens expressed in MM, including adoptive cell therapy, as well the recent studies on checkpoint inhibitors.

Targeting tumor antigens in multiple myeloma

Humoral and cellular immune responses to antigens expressed on myeloma cells have been identified in patients with MM. These include Wilm's tumor 1 (WT1), and cancer-testis antigens such as melanoma-associated antigen 3 (MAGE-A3), MAGE-C2, MAGE-C1/CT7, SSX2 and NY-ESO-1 (64-69). Although it had been postulated that immune deficiency following HCT would prevent the generation of effective anti-tumor immunity, preclinical studies as well as clinical trials have shown that lymphopenic state early post HCT may actually provide an opportunity to skew the recovering immune repertoire towards tumor specific antigens (70-73). In pre-clinical mouse models, irradiation of mice followed by lymphocyte infusion and immunization against tumor antigens resulted in significant increases in T cell responses to these antigens and tumor eradication (70). This study also demonstrated a critical window for optimal responses where both the timing of immunization and lymphocyte infusion in the irradiated host were crucial. These results are further supported by clinical trials in which patients with MM underwent ASCT followed by lymphocyte infusion and immunization (71, 72). In the more recent study, 54 patients with MM underwent ASCT followed by ex vivo stimulated autologous T cells at day 2 after transplantation (71). Twenty-eight patients who were HLA-A0201 underwent immunization before and after transplantation with a multipeptide vaccine against human telomerase reverse transcriptase (hTERT) and survivin. Thirty-six % of immunized patients developed immune responses to the tumor antigen vaccine. Additional studies of tumor immunization are ongoing in patients with MM undergoing ASCT. In one phase I trial, for example, patients with MM undergoing ASCT are being vaccinated with dendritic cells electroporated with CT7, MAGE-A3, and WT1 mRNA (NCT01995708).

Gene modified T cells in multiple myeloma

As noted above, dramatic results have been reported with the use of CAR T cells in ALL and promising results have also been seen in patients with NHL. A recent case report described the use of CD19 CAR T cells following a second ASCT in a patient with MM (74). The patient sustained a CR without evidence of recurrence at 12 months. These results are interesting given the extremely low expression of CD19 on the patient's neoplastic plasma cells. It should be noted, however, that the response needs to be viewed in context of the fact that the patient received the cells following ASCT. Furthermore, preliminary results of this trial (NCT02135406) presented at ASCO in 2015 suggest this patient may be a unique responder, or at least the best responder (75). In contrast, the recently reported study of T cells genetically modified to express a TCR specific for a peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1 showed more consistent positive responses (76). Twenty MM patients received engineered T cells two days after ASCT. Clinical responses were seen in 16 of 20 patients (80%), with a median PFS of 19.1 months. The authors also demonstrated that engineered T cells trafficked to marrow and showed persistence that correlated with clinical activity. One of the known limitations of TCRs compared to CARs is the fact that they are HLA-restricted and can therefore only be used in the patients with a specific HLA unlike CARs that can be sued universally. Other targets under investigation with CAR T cells or NK cells include CS1, a cell surface glycoprotein highly expressed on the surface of myeloma cells (77, 78), as well as CD38, CD138, B cell maturation antigen (BCMA) and kappa light chain (79).

Checkpoint inhibitors in multiple myeloma

PD-1 and its ligands have been shown to be broadly expressed in the myeloma microenvironment and preclinical data supporting the use of checkpoint inhibitors in MM have lead to studies of anti PD-1 antibodies in MM (80-82). However, preliminary results of a phase I study of nivolumab in patients with relapsed or refractory lymphoid malignancies have been relatively disappointing compared to studies in lymphoma (53). Recent data suggests that other PD-1/PD-L1 independent pathways may be more critical in MM, explaining the lack of response to these agents (83).

Future directions

The treatment of MM is evolving rapidly with the introduction of novel agents and combinations. Nevertheless, despite increased rates and depth of response, most patients will not be cured. Early results with new immunotherapy approaches including CARs and TCRs, as well cancer vaccine approaches offer encouraging results that will require validation in larger prospective trials. The potential role of checkpoint inhibitors in MM remains under investigation and their full benefit may require combination studies.

Conclusions

ASCT remains a curative treatment for many patients with hematologic malignancies. Recent studies seeking to enhance immune responses either through the use of CAR T cells targeting CD19 or checkpoint inhibitors have shown remarkable results in patients with leukemia and lymphoma in the non-transplant setting. These approaches have served as a bridge to transplant or have been used as salvage for patients who relapse or progress after transplant. Ongoing studies are examining the role of combining these therapies with stem cell transplantation to further improve outcomes in patients with lymphoma and multiple myeloma.

Acknowledgments

This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748 (M.A.P. and C.S.)

Footnotes

Conflict of Interest Disclosure: M.-A.P. served on advisory boards for Amgen, Merck and Seattle Genetics. C.S. has received consultancy fees from Juno Therapeutics. P.A. has received research funding from Merck, Bristol-Myers Squibb, and consultancy fees from Merck and Infinity Pharmaceuticals.

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