Immunotherapy in hematological malignancies: Current landscape and future directions

INTRODUCTION

Multiple host factors of the immune system significantly impact therapeutic responses and play a significant role in either promoting disease progression or facilitating its regression. Immunotherapy is a therapeutic modality that involves the modulation or activation of the immune system to recognize and eliminate pathological cells. Its primary objective is to activate both the innate and adaptive arms of the immune system to achieve sustained and effective eradication of malignant cells. The immune system plays a central role in controlling hematologic cancers. Innate immune cells, particularly natural killer (NK) cells, provide rapid, non-specific defense against tumor cells, whereas adaptive immunity – through T-cell-mediated cellular responses and B-cell-mediated antibody production – targets malignant cells with high specificity. Tumor cells can evade immune surveillance by exploiting pathways such as programmed cell death protein 1/programmed death-ligand 1 (PD-1/PDL-1) signaling, secreting immunosuppressive cytokines, reducing major histocompatibility complex (MHC) expression, and expanding regulatory T cells (Tregs) that inhibit effector responses. Memory T and B cells contribute to long-term immune monitoring, enhancing the efficacy of treatments like chimeric antigen receptor T (CAR-T) therapy and bispecific T-cell engagers (BiTEs). Effective immunotherapeutic strategies aim to stimulate these immune mechanisms while overcoming tumor-mediated immunosuppression.^[1] Immunotherapeutic strategies are generally classified into two main categories: Passive approaches, which include adoptive cell transfer and monoclonal antibody therapies, and active approaches, such as cancer vaccines and allergen-specific immunotherapies that aim to provoke an endogenous immune response.^[2]

TYPES OF IMMUNOTHERAPY

Immunotherapeutic modalities in hematological malignancies include:^[3]

• Hematopoietic stem cell transplantation (HSCT)

• Monoclonal antibodies (mAbs)

• Antibody-drug conjugates (ADCs)

• BiTEs

• CAR-T therapy

• Immune checkpoint inhibitors (ICI)

• Tumor vaccines

• Oncolytic viruses (OVs).

EVOLUTION OF IMMUNOTHERAPY

Dr. William B. Coley, often referred to as the “Father of Cancer Immunotherapy,” was the first notable figure to use the immune system to treat cancer. In the 1890s, he developed “Coley’s toxins,” a mixture of bacterial products used to stimulate an immune response against tumors. His work laid the foundation for modern cancer immunotherapy.^[4] Allogeneic allo-HSCT is one of the earliest and most established forms of cancer immunotherapy. It was first introduced for clinical use in 1968 by Dr. E. Donnall Thomas, which laid the foundation for modern cellular immunotherapy. His work demonstrated the curative potential of allo-HSCT in hematologic malignancies, was later recognized with the Nobel Prize, and he is also known as the “father of stem cell transplantation” for the same.^[5] Timelines of key milestones in immunotherapy for hematologic malignancies are summarized in Figure 1.^[6]

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Figure 1:

Timeline of key milestones in immunotherapy for hematologic malignancies. MDS: Myelodysplastic syndromes, AML: Acute myeloid leukemia, CAR-T: Chimeric antigen receptor T-cell therapy, R/R: Relapsed or refractory, cHL: Classical Hodgkin lymphoma, ALCL: Anaplastic large cell lymphoma, ALL: Acute lymphoblastic leukemia.

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MECHANISM OF IMMUNOTHERAPY

Immunotherapies function by two main strategies: (1) Directly attacking malignant cells and (2) modulating the host immune response to heighten anti-tumor activity.

KEY MABS IN HEMATOLOGICAL MALIGNANCIES

Rituximab, the first monoclonal antibody approved by the United States Food and Drug Administration (FDA) for cancer treatment, targets the CD20 antigen on B lymphocytes and is the mainstay of treatment for B-cell non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL). In addition, it is also used in chronic GVHD and B-cell acute lymphoblastic leukemia (B-ALL). Rituximab is widely used in combination with chemotherapy regimens, most notably Rituximab + Cyclophosphamide + Doxorubicin + Vincristine + Prednisone (R-CHOP) in B-NHL. In December 2000, the Groupe d’Etude des Lymphomes de l’Adulte released preliminary findings from a randomized controlled trial comparing R-CHOP with CHOP alone in patients aged ≥60 years with advanced-stage DLBCL. The incorporation of rituximab into the CHOP regimen led to significant benefit, with event-free survival improving by 19% and overall survival by 13%.^[13] It has also shown benefit when used with immunomodulatory agents like lenalidomide in B-NHL like follicular lymphoma (FL) and mantle cell lymphoma (MCL). Other anti-CD20 antibodies have since been developed to overcome limitations and enhance efficacy. Obinutuzumab is a glycoengineered type II anti-CD20 antibody with enhanced ADCC activity, first approved for FL (GALLIUM trial),^[14] then subsequently for CLL. Ofatumumab binds a distinct epitope on CD20 with high affinity along with strong CDC and is particularly effective in fludarabine-refractory CLL following COMPLEMENT 1 trial.^[15] Ublituximab is an investigational glycoengineered mAb with potent ADCC, currently under evaluation for R/R CLL and NHL. Ocrelizumab, initially approved for multiple sclerosis, shares structural similarity with rituximab and has shown activity in B-cell malignancies in early clinical studies.^[12]

Alemtuzumab is a mAb against CD52, a pan-lymphocyte marker. The accelerated approval was granted by the FDA on May 7, 2001, for refractory CLL. It is also used in T-cell leukemia/lymphoma, Sezary syndrome, aplastic anemia, and steroid-resistant GVHD. It causes profound lymphocyte depletion, hence used for conditioning before HSCT but carries a high risk of infection and vascular complications.^[16]

Denosumab is a fully human monoclonal antibody targeting RANK-L, approved for use in MM to prevent skeletal-related events. It inhibits osteoclast-mediated bone resorption and is often used as an alternative to bisphosphonates in patients with renal impairment (482 study, XGEVA).^[17]

Daratumumab is a fully human IgG1κ monoclonal antibody targeting CD38, which is highly expressed on plasma cells. It was the first monoclonal antibody approved for MM, initially as monotherapy in heavily pretreated relapsed/refractory patients and later in combination regimens. On June 27, 2019, the FDA approved daratumumab with lenalidomide and dexamethasone (DRd) for newly diagnosed MM patients ineligible for transplant. Approval came from the phase III MAIA trial, which showed significantly improved progression-free survival with DRd compared to Rd alone in 737 patients.^[18]

Other investigational mAbs include zanolimumab (anti-CD4), ublituximab (anti-CD20), ocrelizumab (anti-CD20), epratuzumab (anti-CD22), lumiliximab (anti-CD23), lorvotuzumab mertansine (anti-CD56), and lintuzumab (anti-CD33). These antibodies target distinct antigens in hematological malignancies, but their mechanisms remain investigational, with limited or mixed outcomes reported in clinical trials. Table 1 summarizes mAbs in hematological malignancies.^[11]

KEY ADCS IN HEMATOLOGICAL MALIGNANCIES

Gemtuzumab ozogamicin (GO) is an ADC targeting CD33, linked to calicheamicin through an acid-labile linker. CD33 (Siglec-3) is a transmembrane receptor found on myeloid cells but is absent on normal hematopoietic stem cells, making it a therapeutic target in AML. Once internalized, the linker is cleaved in lysosomes, releasing the toxin that induces DNA damage and cell death. It was first FDA-approved on September 1, 2017, for newly diagnosed and R/R CD33-positive AML in adults and children aged ≥2 years, based on ALFA-0701 trial.^[20,21] Inotuzumab ozogamicin (IO) is an ADC that targets CD22 and delivers a calicheamicin payload through an acid-sensitive linker, allowing intracellular toxin release and DNA damage. CD22 is a sialic acid-binding Ig-like lectin (Siglec) expressed on B-lymphocytes throughout all the stages of development, except plasma cells. It is absent from hematopoietic stem cells and non-lymphoid tissues. CD22 is commonly expressed in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The FDA approved IO on March 6, 2024, for pediatric patients aged ≥1 year with R/R CD22-positive BCP-ALL after the landmark INO-VATE trial.^[22,23]

Key toxicities of both GO and IO are hepatotoxicity and sinusoidal obstruction syndrome.

Brentuximab vedotin is a CD30-directed ADC consisting of a chimeric IgG1 antibody, the cytotoxic agent monomethyl auristatin E (MMAE), and a protease-cleavable linker. Initially approved by the FDA on March 20, 2018, for previously untreated stage III/IV classical Hodgkin lymphoma (cHL) with AVD chemotherapy (ECHELON 1 trial),^[24] its indications now include post–auto-HSCT consolidation (AETHERA trial),^[25] R/R cHL, untreated systemic–anaplastic large cell lymphoma, and CD30-positive peripheral T-cell lymphoma. Common toxicities include peripheral neuropathy, cytopenias, cough, edema, rash, and rare but serious hepatotoxicity.^[26]

Polatuzumab vedotin is an ADC targeting CD79b composed of a humanized IgG1 antibody, MMAE, and a protease-cleavable linker. Upon binding to CD79b – a B-cell surface protein highly expressed in mature B-cell lymphomas – the complex is internalized, and MMAE is released intracellularly, disrupting microtubules and inducing G2/M cell cycle arrest and apoptosis. The FDA granted accelerated approval on June 10, 2019, for its use in combination with bendamustine and rituximab in R/R diffuse large B-cell lymphoma (DLBCL) after ≥2 prior therapies. On April 19, 2023, it was also approved for use with rituximab, cyclophosphamide, doxorubicin, and prednisone) in untreated DLBCL or high-grade B-cell lymphoma (HGBL) with an International Prognostic Index ≥2, based on POLARIX trial.^[27] The most frequent adverse effect is peripheral neuropathy.^[28]

Loncastuximab tesirine is an ADC composed of a humanized anti-CD19 monoclonal antibody linked to a pyrrolobenzodiazepine (PBD) dimer toxin. Following internalization by CD19-expressing cells, the PBD payload induces DNA interstrand crosslinking with minimal distortion, impairing DNA repair and triggering apoptosis. The FDA granted accelerated approval on April 23, 2021, for adult patients with R/R large B-cell lymphoma (LBCL), including DLBCL NOS, transformed DLBCL from indolent lymphomas, and HGBL, after ≥2 prior systemic therapies (LOTIS 2 trial).^[29,30]

Moxetumomab pasudotox is a recombinant immunotoxin composed of an anti-CD22 Ig variable fragment fused genetically to pseudomonas exotoxin A (PE38). This molecule is produced through recombinant DNA technology, unlike other ADCs that use chemical linkers. Upon CD22 binding and internalization, the toxin inhibits protein synthesis through ADP-ribosylation of elongation factor 2, leading to apoptotic cell death. The FDA approved it on September 13, 2019, based on study 1053 (NCT01829711), for adults with R/R hairy cell leukemia (HCL) after ≥2 prior systemic regimens, including a purine nucleoside analogue.^[31,32]

Belantamab mafodotin is an afucosylated, humanized ADC targeting B-cell maturation antigen (BCMA), primarily expressed on malignant plasma cells in MM. The antibody is conjugated through a stable maleimidocaproyl linker to MMAF, a microtubule-disrupting agent. After internalization, MMAF is cleaved and released, inducing cell cycle arrest and apoptosis. It also mediates tumor killing through ADCC and phagocytosis. It received accelerated FDA approval in August 2020 for patients with R/R MM who have received ≥4 prior lines of therapy including a proteasome inhibitor, an IMiD, and an anti-CD38 antibody, after DREAMM-2 trial. Most common adverse effect is epithelial keratopathy.^[33,34]

Table 2^[19] summarizes key ADCs in hematological malignancies.

FDA-APPROVED BITEs

Till date, three BiTEs have been approved by the U.S. FDA for hematologic malignancies:

Blinatumomab, a CD19×CD3 BiTE, was the first approved on December 3, 2014, for treatment of Philadelphia chromosome-negative relapsed or refractory precursor B-ALL (R/R ALL). Then approved for the treatment of adult and pediatric patients with B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥0.1%, based on landmark trials (BLAST, TOWER). Its efficacy in MRD negativity is well established, but its use is limited by the requirement for continuous infusion and neurotoxicity.^[35-37]

Mosunetuzumab, a CD20×CD3 BiTE, has been approved for R/R FL after two or more lines of therapy (GO29781 study). Administered subcutaneously with step-up dosing, it demonstrates durable clinical responses while mitigating cytokine release syndrome (CRS).^[38]

Teclistamab, targeting BCMA and CD3, is approved for triple-class refractory MM. In the landmark trial (MajesTEC-1 trial), it achieved an overall response rate (ORR) of 63.0% and a complete response (CR) rate of 39.4%. CRS and infections remain the most common adverse events.^[39]

EMERGING BITEs

Multiple investigational BiTEs targeting novel antigens have demonstrated efficacy with manageable toxicity profiles.^[40] Talquetamab (GPRC5D×CD3) was approved in August 2023 (MonumenTAL-1 study)^[41] and elranatamab (BCMA×CD3) was approved in August 2023 (MagnetisMM-3)^[42] for the treatment of R/R MM, while glofitamab, a CD20 × CD3 BiTE, was approved in the U.S. in June 2023 for R/R DLBCL (Trial NP30179).^[43] Other emerging BiTEs in the pipeline are linvoseltamab (BCMA×CD3) and cevostamab (FcRH5×CD3).

MECHANISMS OF RESISTANCE

• Downregulation or loss of target antigens such as BCMA

• Functional impairment or exhaustion of T cells

• Presence of immunosuppressive tumor microenvironment (TME).

These mechanisms prevent effective T-cell engagement, activation, and subsequent tumor cell killing.^[44]

FUTURE DIRECTIONS

Advancements in BiTE design are focusing on improving pharmacokinetics, minimizing immunogenicity, and enabling more convenient administration routes such as subcutaneous injection. Ongoing research is exploring combination approaches with checkpoint blockade, immunomodulatory drugs, and CAR-T therapies to enhance efficacy and counteract resistance. Identifying and targeting novel tumor antigens may broaden the applicability of BiTEs across diverse hematologic malignancies.^[44]

FDA APPROVALS

Following the initial FDA approval in 2017 for tisagenlecleucel, CAR T-cell therapies have expanded to treat several other malignancies, which is summarized in Table 3.^[46] The first CAR-T cell therapy in India was administered on June 4, 2021, by a collaborative team from Tata Memorial Hospital (TMH) and IIT Bombay at ACTREC. This clinical trial was supported by BIRAC, which sanctioned funding of INR 18.97 crore.^[47]

TOXICITIES

CAR-T therapy, although highly effective, is associated with serious adverse effects. The most common is CRS, a severe inflammatory reaction characterized by fever, hypotension, hypoxia, and multiorgan dysfunction driven by cytokines such as IL-6 and IFN-γ. Neurotoxicity, initially termed CART-cell-related encephalopathy syndrome, is now standardized as immune effector cell–associated neurotoxicity syndrome (ICANS) by ASTCT. ICANS may manifest as confusion, aphasia, seizures, or cerebral edema, and its severity is graded using the ICE score. Other complications include prolonged cytopenias, heightened infection risk due to immunosuppression, and coagulation abnormalities such as DIC. These toxicities are managed with agents like tocilizumab and corticosteroids, while newer CAR designs incorporate safety switches or IL-6 pathway inhibitors to mitigate adverse effects.^[45]

CAR-T VERSUS BITE

CAR-T therapy is preferred in resource-rich settings, especially when a finite treatment duration is desired, recent CNS involvement is present, or allo-HSCT is not feasible. In contrast, BiTE therapy is more suitable in resource-poor settings, particularly for frail or elderly patients with a high disease burden, rapidly progressive disease, or when prolonged outpatient therapy is acceptable. Both share overlapping toxicities such as CRS and neurotoxicity ICANS. However, CRS and ICANS tend to be earlier in onset, lower grade, and more reversible with BiTEs, while CAR-T therapy is associated with higher-grade, delayed, and sometimes life-threatening toxicities. This distinction reflects differences in pharmacokinetics, with CAR-T cells expanding in vivo, whereas BiTEs have shorter half-lives and are administered continuously, allowing better titration and interruption if toxicity develops.^[48]

TYPES OF TUMOR VACCINES

Peptide/protein-based vaccines: Use tumor-specific antigens such as WT1/PR1 in AML/MDS/CML, DNA+BCL2/tetanus toxoid in myeloma, and idiotype vaccines in FL.

Whole cell-based vaccines: Utilize irradiated tumor cells expressing multiple antigens, used in AML, MDS, CLL, and MM often engineered to secrete GM-CSF to enhance immunity.

Tumor antigen-loaded antigen-presenting cells vaccines: Involve dendritic cells loaded with tumor antigens like WT1 or hTERT AML, DC-myeloma fusion MM, or idiotype-loaded DCs (lymphoma) to activate cytotoxic T cells.

Indications of vaccination strategies include smoldering myeloma, post-chemotherapy remission (CR1) in leukemia/lymphoma/myeloma, following autologous or allogeneic HSCT, and in combination with novel agents during relapse. Future directions aim to enhance efficacy by combining vaccines with checkpoint inhibitors, CAR-T cells, immunomodulatory agents, or radiation.

CONCLUSION

Immunotherapy is a therapeutic approach that aims to target or manipulate the host’s adaptive and innate immune response, leading to long-lived elimination of diseased cells. Immunotherapy includes mAbs including ADCs, BiTEs, CAR-T therapy, ICIs, tumor vaccines, and oncolytic virus. ADCs are preferred over Naked mAbs due to their higher efficacy and cytotoxicity. CAR T is preferred in resource-rich settings with relapse/refractory transplant-ineligible patients, with recent CNS disease, in whom a finite duration of treatment is desired (R/R ALL, DLBCL, FL, HGBCL, PMBCL, MCL, MM). BiTE is preferred in resource-poor settings with relapse/refractory, frail/old patients, with high tumor burden (R/R B-ALL, FL, MM). PDL1 inhibitors are attractive treatment options in R/R CHL, PMBCL. Newer immunotherapies in development include tumor vaccines and OV.