Immunotherapy in haematological malignancies

Authors:

Details:

  1. Olivia Newton John Cancer and Wellness Centre, Austin Health, Heidelberg, Australia.
  2. Olivia Newton John Cancer Research Institute, La Trobe University, Heidelberg, Australia.
  3. Monash University, Melbourne, Australia.
  4. Eastern Health, Box Hill, Australia.

Abstract

Haematological malignancies are a heterogenous group of diseases mostly of immunological origin. Immunotherapies such as allogeneic stem cell transplantation and monoclonal antibodies have been an essential part of managing haematological malignancies for decades, though recent understanding of tumour and microenvironment biology has led to the development of highly effective targeted therapies. Inhibiting immune checkpoints such as programmed death-1 (PD-1) and its ligand (PD-L1) have yielded remarkable results in some highly refractory lymphoma subtypes such as relapsed classical Hodgkin Lymphoma. Autologous T-cells with chimeric antigen receptors (CARs) are highly effective in B-lineage acute lymphoblastic leukaemia (B-ALL) and appear promising in diffuse large B cell lymphoma (DLBCL) and myeloma. Bispecific antibodies such as blinatumomab are superior to salvage chemotherapy for relapsed/refractory B-ALL and have become standard of care. However, significant challenges remain in cost, deliverability and manufacture of some of these products. Certain haematological malignancies such as myelodysplastic syndrome and acute myeloid leukaemia remain poorly responsive to current immunotherapy, though new agents show promising pre-clinical data. Immunotherapy is a pillar of management for haematological malignancies and are likely curing a subset of patients previously considered incurable; the clinical challenge is determining how to employ these therapies for maximal benefit and minimal toxicity.


Haematological malignancies represent over 100 distinct diseases.1 The incidence is increasing and is currently 40 per 100,000.2,3 Myelosuppressive chemotherapy is central to treatment, though immune manipulation has been standard management for selected haematological cancers since the advent of allogeneic stem-cell transplantation (SCT), utilising a graft-versus-tumour effect to control chemotherapy-refractory disease. Next-generation immune therapies which target T-cell mobilisation are efficacious in multiple haematological malignancies. Mechanisms of action in haematological malignancies are complex as most of these diseases have an immunological origin. Immunotherapy has brought new challenges to clinical practice. Assessing response with conventional imaging modalities is problematic due to tumour-associated inflammation mimicking disease progression and the delayed nature of responses. Immune-related toxicities attributable to these agents have necessitated new monitoring and management strategies. Additionally, certain agents (e.g. PD-1/PD-L1 inhibitors) require appropriate patient selection to reduce the risk in patients with existing autoimmune diseases. Haematological malignancies represent over 100 distinct diseases.1 The incidence is increasing and is currently 40 per 100,000.2,3 Myelosuppressive chemotherapy is central to treatment, though immune manipulation has been standard management for selected haematological cancers since the advent of allogeneic stem-cell transplantation (SCT), utilising a graft-versus-tumour effect to control chemotherapy-refractory disease. Next-generation immune therapies which target T-cell mobilisation are efficacious in multiple haematological malignancies. Mechanisms of action in haematological malignancies are complex as most of these diseases have an immunological origin. Immunotherapy has brought new challenges to clinical practice. Assessing response with conventional imaging modalities is problematic due to tumour-associated inflammation mimicking disease progression and the delayed nature of responses. Immune-related toxicities attributable to these agents have necessitated new monitoring and management strategies. Additionally, certain agents (e.g. PD-1/PD-L1 inhibitors) require appropriate patient selection to reduce the risk in patients with existing autoimmune diseases. 

Scores of novel immunotherapeutics are under active clinical investigation. This review focuses on the most promising evidence for therapies in haematological malignancies as well as potential biomarkers of response.

Programmed cell death-1 (PD-1) and PD-1 ligand (PDL-1) inhibitors

Activation of the PD-1 axis leads to reversible inhibition of T-cell activation and proliferation.4 Tumours can evade the host immune response by expressing PD-L1, thereby engaging PD-1 on T-cells in the microenvironment and suppressing T-cell activity.5 Modulation of the PD-1/PD-L1 axis has led to sustained remissions in a range of solid tumours.6 

Likewise, PD-1/PD-L1 modulation has significant efficacy in certain lymphoma subtypes. Responses are variable for reasons not fully elucidated. Overexpression of PD-1 and/or PD-L1 within the microenvironment, and on malignant cells, vary between lymphoma subtypes. However, tumours which inherently overexpress these proteins appear to respond. In some lymphoma subtypes, preliminary data suggest PD-1/PD-L1 protein overexpression may correlate with prognosis and possibly response, however this is not universal and likely other mechanism contribute.7 Amplification of 9p24, the locus of the PD-L1 and PD-L2 genes, causes upregulation of PD-L1 and PD-L2 and are described in over 85% of classical Hodgkin lymphoma (cHL), as well as a proportion of follicular lymphoma (FL) and Diffuse large B cell lymphoma (DLBCL).8,9   

Detailed review of toxicities is beyond the scope of this review, however most patients with haematological malignancies receiving PD-1 inhibitors at relapse experience only grade 1-2 toxicity. Deaths from immune phenomena are a rare outcome.10-12 Favourable toxicity profiles allow potential combination with other agents, though it is unclear to what degree immunosuppressive chemotherapy negates their action.13

Classical Hodgkin lymphoma 

Classic Hodgkin lymphoma (cHL) is a rare malignancy characterised by relatively few tumour cells (Hodgkin or Reed-Sternberg (HRS) Cells) surrounded by a redundant inflammatory infiltrate, suggesting immune evasion plays an important pathogenic role.1 The high rate of 9p24 amplification and subsequent PD-L1 expression provides solid biological rationale for PD-1/PD-L1 axis inhibition.8

An initial phase one study of nivolumab in 23 relapsed or refractory (R/R) cHL patients demonstrated overall response rates (ORR) exceeding 85% (95% CI 66-97%).14,15 PD-1 inhibitor efficacy in cHL appears to be a class effect, with subsequent studies of nivolumab and pembrolizumab yielding similar ORR (table 1). CR rates were variable (9-28%) with significant discordance between investigator-reported CR and CR by central radiological review,10,11 highlighting the challenges of assessing response using conventional imaging modalities such as FDG-PET/ CT.16 

Table 1: Overview of promising immunotherapy efficacy in haematological malignancies

Agent

Target

Disease (n)

Phase

% ORR [95%CI]

% CR

Survival

Nivolumab10

PD-1

R/R cHL (80)

II

66 [55-76]

9-28

Median PFS 10 months

Pembrolizumab11

PD-1

R/R cHL (210)

II

69 [62.3-75.2]

22

PFS 63% at 9 months

Nivolumab21

PD-1

R/R DLCBL (11)

Ib

34

9

NR

Pidilizumab24

? PD-1

R/R DLBCL post AuSCT (66)

II

51

35

PFS 72% at 16m

Pembrolizumab + rituximab28

PD-1

R/R FL (20)

Ib

65

50

NR

Nivolumab21

PD-1

R/R FL (10)

Ib

40

10

NR

Pembrolizumab33

PD-1

R/R PMBL (18)

Ib

41

11

Median PFS not reached at 12 months

Pembrolizumab36

PD-1

R/R NK/T cell lymphoma (7)

Retro-spective

100

71

NR

PD-1 = Programmed death-1, R/R = Relapsed or refractory, cHL = Classical Hodgkin Lymphoma, ORR = overall response rate, CR = complete response rate, PFS = progression free survival, DLBCL = diffuse large B cell lymphoma, NR = Not reported, FL = Follicular lymphoma, PMBL = primary mediastional B cell lymphoma

In contrast to rapid chemotherapy responses, median time-to-response was three months, and some patients had ongoing deepening response beyond nine months.10,11 Responses also appear to be durable, although longer follow-up is required. 

The potency of these agents in cHL is remarkable particularly in heavily pre-treated patients, many with relatively redundant immune systems due to disease and prior myelosuppressive therapies. As in melanoma, combination with other checkpoint inhibitors may augment efficacy at the expense of higher immune-related adverse event (irAE) rates.17 A phase one study in cHL of ipiliumumab (CTLA-4 inhibitor) plus nivolumab has shown a favourable safety profile however efficacy data from larger studies are awaited (table 2).18

Table 2: Key active trials PD-1 or PD-L1 inhibitors in haematological malignancies

Drug

Disease

Timepoint/combination

Phase

Clinicaltrials.gov

Durvalumab

BNHL

R/R with JCAR014

Ib

NCT02706405

Durvalumab

NHL or CLL

R/R, multiple combinations

II

NCT02733042

Durvalumab

DLBCL

Up-front, combination with R-CHOP or R2-CHOP

II

NCT03003520

Durvalumab

DLBCL

Following AuSCT

II

NCT03241017

Durvalumab

DLBCL

R/R, combination with tremilimumab or AZD9150

II

NCT02549651

Durvalumab

MDS

Up-front with azacitidine

II

NCT02775903

Durvalumab

MDS

Failed Azacitidine, combination oral azacitidine

II

NCT02281084

Durvalumab

Myeloma

R/R combination with daratumumab

II

NCT03000452

Durvalumab

Myeloma

R/R with lenalidomide +/- dexamethasone

I

NCT02616640

Durvalumab

Myeloma

Up-front with lenalidomide +/- dexamethasone

I

NCT02685826

Atezolizumab

DLBCL or FL

Up-front, multiple combinations

Ib/II

NCT02596971

Atezolizumab

DLBCL

R/R combination with KTE-C19

I-II

NCT02926833

Atezolizumab

DLBCL and FL

R/R with tazemetostat or obinutuzumab

I

NCT02220842

Atezolizumab

DLBCL and FL

R/R with obinutuzumab, and polatuzumab-vedotin

II

NCT02729896

Atezolizumab

NHL

R/R with venetoclax and obinutuzumab

II

NCT03276468

Atezolizumab

cHL

R/R

II

NCT03120676

Atezolizumab

FL

R/R with lenalidomide and obinutuzumab

I

NCT02631577

Atezolizumab

Asymptomatic myeloma

Up front

I

NCT02784483

Atezolizumab

Myeloma

R/R +/- lenalidomide +/- daratumumab

I

NCT02431208

Atezolizumab

AML

Consolidation therapy for patients in remission

I/II

NCT03154827

Atezolizumab

AML

R/R or unfit for induction in combination with gaudecitabine

I

NCT02892318

Atezolizumab

CLL

R/R with ibrutinib and obinutuzumab

II

NCT02846623

Avelumab

PTCL

R/R

II

NCT03046953

Avelumab

DLBCL

Up-front combination with R-CHOP

Ib

NCT03244176

Avelumab

cHL

R/R

I

NCT02603419

Avelumab

DLBCL

R/R, multiple combinations

Ib-III

NCT02951156

Avelumab

AML

R/R with azacitidine

I/II

NCT02953561

Pembrolizumab

PCNSL

R/R

II

NCT02779101

Pembrolizumab

cHL

R/R combination with Radiation

II

NCT03179917

Pembrolizumab

FL

R/R with rituximab

II

NCT02446457

Pembrolizumab

cHL

R/R with AMF13

I

NCT02665650

Pembrolizumab

cHL

R/R with B-V

III

NCT02684292

Pembrolizumab

cHL, NHL

R/R with Lenalidomide

I/II

NCT02875067

Pembrolizumab

PMBL, Richter syndrome

R/R

II

NCT02576990

Pembrolizumab

Lymphoma

Following AuSCT

II

NCT02362997

Pembrolizumab

Lymphoma

R/R with Entinostat

II

NCT03179930

Pembrolizumab

NK/T cell lymphoma

R/R

II

NCT03107962

Pembrolizumab

cHL, DLBCL, FL

R/R with vorinostat

I

NCT03150329

Pembrolizumab

cHL

R/R with ICE salvage chemotherapy

II

NCT03077828

Pembrolizumab

Low-grade B-NHL or CLL

R/R with ibrutinib or idelalisib

II

NCT02332980

Pembrolizumab

cHL

Up-front with AVD

II

NCT03226249

Pembrolizumab

B-NHL

R/R with ibrutinib

I

NCT02950220

Pembrolizumab

PCNSL, GZL, extranodal DLBCL

R/R

II

NCT03255018

Pembrolizumab

DLBCL, 3b FL

Up-front with R-CHOP

II

NCT02541565

Pembrolizumab

CTCL, PTCL

R/R with decitabine and pralatrexate

I

NCT03240211

Pembrolizumab

Haem malignancies

R/R following allogeneic SCT

I

NCT02981914

Pembrolizumab

B-ALL

R/R with blinatumomab

Ib/II

NCT03160079

Pembrolizumab

ALL

MRD positive following chemotherapy

II

NCT02767934

Pembrolizumab

MF and Sezary syndrome

R/R with interferon gamma-1b

II

NCT03063632

Pembrolizumab

Smouldering myeloma

Up-front

I

NCT02603887

Pembrolizumab

Myeloma

 R/R with daratumumab

II

NCT03221634

Pembrolizumab

Myeloma

MRD following induction

II

NCT02636010

Pembrolizumab

AML

R/R with decitabine

I/II

NCT02996474

Pembrolizumab

AML

R/R or unfit for induction with azacitidine

II

NCT02845297

Pembrolizumab

B-ALL

R/R with blinatumomab

I/II

NCT03160079

Pembrolizumab

AML

Consolidation for patients in remission

II

NCT02708641

Pembrolizumab

AML

R/R with cytarabine

II

NCT02768792

Pembrolizumab

ALL

MRD+ following induction

II

NCT02767934

Pembrolizumab

MPN

Up front

II

NCT03065400

Nivolumab

PCNSL and PTL

R/R

II

NCT02857426

Nivolumab

cHL

R/R with B-V

II

NCT02572167

Nivolumab

FL

Up-front with rituximab

Ib

NCT03245021

Nivolumab

cHL

R/R with ibrutinib

II

NCT02940301

Nivolumab

cHL

R/R with B-V +/- ipilimumab

II

NCT03057795

Nivolumab

cHL

Up-front following ABVD

I

NCT03033914

Nivolumab

cHL

R/R plus ICE salvage chemo

II

NCT03016871

Nivolumab

cHL

Up-front plus AVD

II

NCT03004833

Nivolumab

PTCL

R/R

II

NCT03075553

Nivolumab

Aggressive B-NHL

R/R +/- varilumab

II

NCT03038672

Nilvolumab

cHL or B-NHL

R/R with lenalidomide

I/II

NCT03015896

Nivolumab

HTLV-T cell leukaemia lymphoma

R/R

II

NCT02631746

Nivolumab

DLBCL

R/R with Bendamustine, gemcitabine, rituximab

I/II

NCT03259529

Nivolumab

Early stage cHL

Up-front with B-V and AVD

II

NCT03233347

Nivolumab

NHL

R/R with B-V

I/II

NCT02581631

Nivolumab

Elderly cHL

Up front with B-V

II

NCT02758717

Nivolumab

cHL

R/R +/- B-V

III

NCT03138499

Nivolumab

EBV-LPD

R/R

II

NCT03258567

Nivolumab

CML

R/R with dasatinib

I

NCT02819804

Nivolumab

B-ALL

R/R with blinatumomab +/- ipilimumab

I

NCT02879695

Nivolumab

AML

Consolidation therapy in remission post induction

II

NCT02532231

Nivolumab

CLL

R/R with ibrutinib

II

NCT02420912

Nivolumab

AML

R/R with ipilimumab or azacitidine

II

NCT02397720

Nivolumab

MDS/AML

Up-front with idarubicin and cytarabine

I/II

NCT02464657

Nivolumab

Ph+ ALL

R/R with dasatinib

I

NCT02819804

Nivolumab

B-ALL

R/R with blinatumomab +/- ipilimumab

I

NCT02879695

Nivolumab

Myeloma

R/R with elotuzumab +/- pomalidomide

II

NCT03227432

Nivolumab

Smouldering myeloma

Up front with lenalidomide and dexamethasone

II

NCT02903381

Nivolumab

Myeloma

R/R with daratumumab +/- lenalidomide and dexamethasone

II

NCT03184194

Nivolumab

Myeloma

Post AuSCT with ipilimumab

I/II

NCT02681302

BGB-A317

cHL

R/R

II

NCT03209973

BGB-A317

B-NHL

R/R with BGB-3111

I

NCT02795182

PD-1 = Programmed death-1, PD-L1 = Programmed death-1 ligand, NHL = non-Hodgkin lymphoma, R/R = Relapsed or refractory, cHL = Classical Hodgkin Lymphoma, DLBCL = diffuse large B cell lymphoma, FL = Follicular lymphoma, PMBL = primary mediastional B cell lymphoma, ALL = Acute lymphoblastic leukaemia, CML = chronic myeloid leukaemia, EBV-LPD = Epstein-Barr virus related lymphoproliferative disease, HTLV = Human T cell leukaemia vius, PTCL = peripheral T cell lymphoma, PCNSL = primary CNS lymphoma, PTL = primary testicular lymphoma, MF = mycosis fungoides, CTCL = cutaneous T cell lymphoma, GZL = grey-zone lymphoma, CLL = chronic lymphocytic leukaemia, AML = acute myeloid leukaemia, MPN = myeloproliferative neoplasms

Diffuse large B cell lymphoma 

Diffuse large B cell lymphoma (DLBCL) is a clinically and biologically heterogenous disease, with multiple histological subtypes.1,19 Despite therapeutic advances, up to 30% of patients will succumb to their disease.20 PD-L1 is variably expressed in DLBCL, more commonly in subtypes such as T-cell rich (TCR)-DLBCL, Activated B cell (ABC)-DLBCL, Epstein Barr Virus (EBV) associated DLBCL and monomorphic post-transplant lymphoproliferative disease (PTLD).9 

Several small studies have evaluated PD-1 inhibition in unselected DLBCL with ORR of 30-40% (table 1).21 Results are awaited from larger phase two studies (NCT02038933). Pidilizumab was initially reported to be a PD-1 inhibitor, however the mechanism of action is now under review; results of a phase 2 study post AuSCT are included for completeness (table 1).22-24

Follicular lymphoma

Follicular lymphoma (FL) is the most common low-grade NHL. Considered incurable in the majority, it frequently follows an indolent course with a median survival of ~14 years, though a small subset follow an aggressive course and succumb much earlier. The TME composition demonstrates prognostic import and is a potential therapeutic target.25-27 While PD-L1 expression on FL tumour cells is rare, it is detected frequently on the tumour associated macrophages in the TME and PD-1-positive tumour-infiltrating lymphocytes (TILs) are also common.27,28 The host immune response has a significant role in FL as evidenced by spontaneous remissions, abscopal responses to radiotherapy and a graft-versus-lymphoma effect following allogeneic SCT.29,30,31 

There is single-agent activity in R/R FL,21 and combination with rituximab appears to be synergistic  (table 1).28 The tolerability of rituximab with pembrolizumab was favourable, providing rationale to study a PD-1 inhibitor/rituximab combination in the up-front setting, which is currently underway (table 2). 

Rare lymphoma types

PD-1/PD-L1 inhibition has shown promising results in several rare NHL subtypes, although data are from early phase studies or small retrospective series (table 1), focusing on diseases with frequent 9p24 amplifications, such as Primary Mediastinal B-cell lymphoma (PMBL), Grey Zone lymphoma (GZL), NK/T-cell lymphomas, Richter’s transformation, Primary CNS (PCNSL) and Primary Testicular lymphomas (PTL). 

PMBL shares phenotypic features with DLBCL but frequently exhibits 9p24 amplifications.8 Though infrequent, relapses usually respond poorly to salvage chemotherapy.32 A recent phase 1b study (n=18) using pembrolizumab demonstrated 41% ORR including 2 CRs whose remissions appear durable.33 A subsequent phase 2 study (NCT02576990) has completed recruitment with results awaited. 

GZL has features intermediate between PMBL and cHL and shares frequent 9p24 amplification.34 To date, data are limited to case series though there is at least one report of a patient with R/R disease achieving CR.35 

NK/T cell lymphomas are rare EBV-driven T-cell malignancies which are commonly PD-L1 positive. A recent series of 7 R/R patients treated with pembrolizumab demonstrated 100% ORR, with 5/7 CR. Reponses appear to be sustained at early follow-up.36 

PCNSL and PTL have similar genetic signatures and often display 9p24 amplifications and PD-L1 expression. A recent case series of five patients demonstrated impressive response rates in R/R disease to nivolumab, including 4 CRs, 3 of which have been sustained beyond 12 months.37

Angioimmunoblastic T-cell lymphoma universally expresses PD-1 consistent with its follicular T-helper origin, though outcomes from PD-1 inhibition have not been reported.9

Many additional studies are currently investigating PD-1/PD-L1 inhibition in lymphoma and are summarised in table 2.

Other haematologic malignancies

Accrual to large phase 3 studies was recently suspended in multiple myeloma using pembrolizumab in combination with lenalidomide or pomalidomide (NCT02579863; NCT02576977) due to increased numbers of deaths in the immunotherapy arms.38 Further results from other studies are awaited (table 2). Acute myeloid leukaemia (AML) and myelodysplasia (MDS) stem cells demonstrate variable expression of PD-L1, and T-cells in the microenvironment have increased expression of PD-1 compared to normal controls.39 In MDS, the combination of azacitidine plus nivolumab yielded ORR of 69% though single-agent results are disappointing (0/15 responses).40 No responses were seen in azacitidine-refractory MDS using atezolizumab alone or in combination with azacitidine.41 In R/R AML, ORR of 53% with 18% CR was achieved in patients treated with azacitidine plus nivolumab.42

Chimeric Antigen Receptor (CAR-T) cells

T-cells can be engineered to express modified T-cell receptors (TCR) with specificity for tumour-associated antigens (figure 1). A key example is the development of CARs directed against the pan-B-cell marker CD19 for use in patients with B-acute lymphoblastic leukaemia (B-ALL). The extraordinary success of this therapy in the R/R setting has led to FDA approval in the USA. Multiple generations of CAR-T cells have been developed to enhance the activity and persistence of T-cells through the addition of co-stimulatory domains.43 Production of ex-vivo autologous CAR-T cells has been the predominant approach but this is stymied by the frequent difficulties encountered as a result of T-cell dysfunction due to prior therapies, long manufacturing time and cost. This has hampered availability and applicability in patients with rapidly progressive disease. Off-the-shelf products from healthy T-cell donors may overcome these issues but the safety of this approach is currently unproven. 

Figure 1: Autologous manufacture of CAR-T cells

 

 

 

 

 

Major toxicities reflect the underlying mechanism of action of CAR-Ts. Healthy cells expressing the antigen specific for the CAR may be destroyed in addition to malignant cells. The B-cell specificity of CD19 is attractive as a therapeutic target not only due to its frequent expression in B-cell malignancies, but also the ability to replace immunoglobulin in those patients where healthy B-cells are also destroyed. Cytokine release syndrome (CRS) shortly after infusion is also common and potentially life-threatening. Driven by rapid rises in IL-6, the severity appears related to disease burden. Early administration of the anti-IL6 MoAb tocilizumab is highly effective in preventing long-term sequelae and death.43,44 Self-limiting encephalopathy and seizures can occur attributed to high cytokines levels and presence of CAR-T cells in the CNS.45,46 Deaths from neurological toxicity recently halted production of the Juno product JCAR-015.

B acute lymphoblastic leukemia

CAR-T cells have been most extensively studied in R/R B-ALL. Several groups have reported outcomes in both adult and paediatric patients, with impressive results for a heavily pre-treated and highly refractory cohort (table 3).44,47-54 

Table 3: Key clinical trials with CAR-T cell

Product

Target

Disease (n)

Phase

ORR

CR (MRD neg)

Survival

CTL-019 CAR-T44

CD19

R/R B-ALL (30)

I

90

90

6-month EFS 67%

CTL-019 CAR-T52

CD19

R/R B-ALL (35)

II

69

69 (62 MRD neg)

Median RFS not reached at 6 months

CTL-019 CAR-T51

CD19

R/R B-ALL (57)

II

83

83 (83 MRD neg)

NR

KTE-1956,60

CD19

R/R DLBCL (111)

II

82

54

PFS 44% at 9 months

CTL-01957

CD19

R/R DLBCL (141)

II

59

43

Median RFS not reached at 3 months

BB212163

BCMA

R/R Myeloma (11)

I

100

36

NR

LCAR-B38M64

BCMA

R/R Myeloma (22)

I

100

27

All responses sustained at median 4 months

CARCD12362

CD123

AML

Preclinical

N/A

N/A

N/A

FLT3-CAR T61

FLT3

AML

Preclinical

N/A

N/A

N/A

CAR = chimeric antigen-receptor, R/R = Relapsed or refractory, ALL = acute lymphoblastic leukaemia, ORR = overall response rate, CR = complete response rate, MRD = minimal residual disease, EFS = event-free survival, RFS = relapse-free survival, PFS = progression free survival, DLBCL = diffuse large B cell lymphoma, NR = Not reported, BCMA = B cell maturation antigen, AML = acute myeloid leukaemia

Durable responses are common, with most relapses either being due to CAR-T cell loss or relapsing with a CD19-negative clone.50 At least some patients previously considered incurable are now potentially cured. Employing CAR-T cells in morphologic CR with minimal residual disease (MRD) may produce more favourable results.55

Other haematological malignancies

CD19 CARs for R/R DLBCL are active with favourable responses compared to historical controls from salvage chemotherapy (ORR 59-82% vs 26%, table 3).56-59 The phase 2 registration study was recently published and has led to FDA approval for this indication.60

CAR-T cells for AML with specificity for CD123 and FLT3 are effective in pre-clinical models (table 3).61,62 CARs targeting B-cell maturation antigen (BCMA) in R/R myeloma currently have an ORR of 100% which requires urgent validation in larger studies (table 3).63,64

Bi-specific antibodies (BsAbs)

BsAbs have two domains capable of binding antigen to facilitate T-cell engagement with target cells, effectively combining the role of tumour targeting MoAbs and T-cell mobilising immunotherapies. Though multiple different formats of BsAbs are being developed, the most advanced are bispecific T-cell engagers (BiTEs) and dual-affinity retargeting antibodies (DARTs) which contain only the variable heavy-chain and variable light-chain portions of an antibody (figure 2).65 Blinatumomab is a BiTE construct and is the most advanced of the BsAbs, engaging the T-cell surface antigen CD3 with the B-cell marker CD19, though other specificities are in development. The DART format is more stable and may have more in vitro efficacy.66

Figure 2: Antibody constructs

Figure 2a: Monoclonal antibody

 

 

 

 

 

Figure 2b: BiTE and DART

 

 

 

 

 

Blinatumomab

Blinatumomab’s specificity for CD3 and CD19 provides clinical utility in B-cell malignancies. Toxicity of blinatumomab is similar to CAR-T cell therapy; CRS and neurological toxicity are most notable, though delivery as a constant 24-hour infusion for four weeks has significant logistical implications.67

Acute lymphoblastic leukaemia

A randomised phase three study in R/R B-ALL demonstrated superiority of blinatumomab over salvage chemotherapy for all outcomes including OS (table 4).68 The majority relapsed by 15-18months, suggesting cure rates of blinatumomab alone are low.69 However, higher CR rates and MRD negativity may translate into better post-allogeneic SCT outcomes for eligible patients.70 The ability of blinatumomab to convert patients in morphologic CR but MRD-positive to MRD-negative in 80% of cases may establish its role as a bridge to allogeneic SCT.71 Results from earlier studies are summarised in table 4.67

Table 4: Key clinical trials BiTEs and DARTs

Product

Target

Disease (n)

Phase

ORR%

CR/MRD negative

Survival (months)

Blinatumomab vs salvage chemotherapy68

 

CD3/CD19

R/R B-ALL (405)

III

CR 44 vs 25 (p<0.001)

MRD neg 76% vs 48% if in CR

RFS 7.3m (95% CI 5.7-9.9) vs 4.6m (95% CI 1.8-19.0)

Blinatumomab67

CD3/CD19

R/R B-ALL (189)

II

CR 43% (95% CI 36-50)

MRD neg 82% if in CR

RFS 5.9m (95%CI 4.8-8.3) for responders

Blinatumomab72

CD3/CD19

R/R DLBCL (21)

II

43

19

Median PFS 3.7m

Blinatumomab73

CD3/CD19

R/R B-NHL

(11 DLBCL)

(15 FL)

(7 MCL)

II

DLBCL 55

FL 80

MCL 71

DLBCL 36

FL 40

MCL 43

RFS  13m

MGD00676

CD3/CD123

AML

I

NR

NR

NR

BiTE = Bispecific T cell engager, DART = dual-affinity retargeting, R/R = Relapsed or refractory, ALL = acute lymphoblastic leukaemia, ORR = overall response rate, CR = complete response rate, MRD = minimal residual disease, EFS = event-free survival, RFS = relapse-free survival, PFS = progression free survival, DLBCL = diffuse large B cell lymphoma, NR = Not reported, AML = acute myeloid leukaemia, FL = follicular lymphoma, MCL = Mantle cell lymphoma

Non-Hodgkin lymphoma

In heavily pre-treated R/R DLBCL, FL and Mantle Cell Lymphoma (MCL) patients, blinatumomab also has efficacy (table 4).72,73 As with B-ALL, it is unclear if blinatumomab will be best be used as a definitive salvage or as a bridge to another therapy such as SCT.74 

Acute myeloid leukaemia

DARTs for AML are currently in development, the most promising is the CD3xCD123 molecule.75,76 A phase 1 clinical trial is currently recruiting for MGD006 (NCT02152956, table 4).

Challenges identifying biomarkers of response

Despite promising results, a significant proportion of patients do not respond to immunotherapeutics. Our ability to predict response to these agents continues to develop, though some challenges remain. The development of biomarkers predicting response is evolving in all cancers, and in haematological malignancies certain features such as composition of the TME,77,78 expression of PD-L1/PD-1 on the tumour cells or within the TME, and the presence of 9p24 abnormalities are prognostic, particularly in some lymphoma subtypes.7 In cHL, the primary mechanism is CD4+ T-Cells interacting with MCHII on PD-L1-expressing HRS cells, and expression of these markers is predictive of response.79

However, it remains unclear if these mechanisms are at play in other lymphoma subtypes. Underlying mechanisms of overexpression also vary, e.g 9p24 amplification in malignant cells, versus TIL PD-1 positivity in the microenvironment, and therefore their role in predicting response may differ. Due to the complexity of biomarker interpretation, selection of patients for PD-1 inhibitors based on simple overexpression of the target proteins via immunohistochemistry is not currently warranted.

Challenges and future directions

Immunotherapy is a powerful addition to the therapeutic armamentarium for haematological malignancies and is becoming a standard option in malignancies such as R/R cHL and B-ALL and potentially FL, DLBCL, NKTCL, PMBCL and PCNSL. Toxicities are manageable and closely reflect the agents’ mechanism of action. However, several unanswered questions remain. It is unclear if prior immunosuppressive chemotherapy dampens the efficacy of these treatments or if their use earlier in the disease course may improve efficacy. There are also economic challenges using these drugs upfront for diseases already well-served by relatively inexpensive chemotherapy, such as cHL. 

Direct combination of immune-stimulating PD-1/PD-L1 inhibitors with immunosuppressive chemotherapy for many cancers is already being trialled; however, results will need to be interpreted with caution due to the potentially antagonistic effect of these two therapeutic approaches. Creative trial designs involving sequential delivery using PD-1/PD-L1 inhibitor “pre-phase” and maintenance treatment appear more logical.

CAR-T cells and BiTES targeting CD19 are remarkably effective in selected disease types, however logistics of manufacture and administration need to be overcome. AML remains an area of need, though there are issues identifying ubiquitous antigens present on all subtypes and the problematic consequences of targeting myeloid progenitor antigens leading to unacceptable toxicity such as bone marrow aplasia. T-cell malignancies face the issue of self-targeting associated with T-cell directed immunotherapies.

Finally, monitoring responses to immunotherapy (in practice and in clinical trials) is an ongoing challenge. Those analysing PET/CT responses to PD-1/PD-L1 inhibition face potential false positive results. For CAR-T cells and blinatumomab, false negatives are more common, such as early CD19-negative relapses that may be missed if a CD19-negative gating strategy is employed by flow cytometry. Revised criteria have been developed, though are difficult to universally apply.80

Conclusion

Subgroups of haematological malignancy have demonstrated very favourable and durable responses to immunotherapy. Indeed, the possibility of cure for some highly refractory and previously incurable diseases has been realised. Rational trial designs are warranted to avoid deleterious drug interactions. Improving patient selection and development of effective biomarkers remain a research priority while simultaneously establishing the best strategy to incorporate their use within current treatment paradigms.

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