Immunotherapy comes of age for blood cancers
The recent approval of nivolumab for the treatment of relapsed classical Hodgkin Lymphoma (cHL) has brought the tumor micro environment into the limelight and has focused attention specifically on the recruitment of host immunity in the treatment of blood cancers. The approval was based on an impressive 87% response rate in cHL patients who had failed both autologous stem cell transplant as well as brentuximab vedotin . Pembrolizumab and other similar agents are also showing activity in cHL and several other hematologic malignancies. By way of side effects, patients have suffered from a wide plethora of autoimmune issues especially regarding the endocrine system but autoimmune pneumonitis and colitis have led to termination of therapy in 2–5 % of patients. Some responses have persisted in spite of termination, but there is no consensus on when to stop these agents and if the responses are durable in most patients.
Programmed cell death-1 receptor and cytotoxic T-lymphocyte-associated protein 4 inhibitors
The programmed cell death-1 (PD-1) receptor and its ligands PD-L1 and PD-L2 as well as the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathway are key regulators of the physiologic immune response and play an important role in promoting self-tolerance and preventing autoimmunity. The inhibitory effect of PD-1 is accomplished through a dual mechanism of apoptosis in antigen-specific Tcells while simultaneously reducing apoptosis in regulatory T cells (Tregs). Similarly, upon activation the CTLA-4 receptor sends an inhibitory signal down the activated T cell and turns off the switch, halting an activated cytotoxic T cell in its tracks. Without these checkpoints in place our immune response to even an insect bite could result in an unbridled immune reaction that could consume normal tissue, leading to widespread cytokine activation, fevers, inflammation, and even death. Cancer cells have found a way to recruit these mechanisms and evade an immune response in spite of antigenic differences between normal and malignant cells. Armand et al have reported that the malignant Reed Sternberg cells in cHL actively modify the PD-1 pathways via multiple mechanisms, thus blocking the host immune response . 9p24.1, a common chromosomal change in cHL, has been shown to increase the gene dose of PD-1 ligands PD-L1 and PD-L2 and there is increased expression of PD-1 driven by the Epstein-Barr virus (EBV) in EBV-associated cHL. It is hypothesized that the T cells in the tumor microenvironment are in a state of exhaustion due to overexpression of PD-1 and its ligands. Immune checkpoint inhibitors such as nivolumab and other antibodies against PD-1, PD-L1, and PD-L2 interrupt the interaction of PD-1 with its ligand and reverse this exhausted state, resulting in the recruitment of the innate immune system and a much needed immune reaction against the malignant cell. In the cHL study mentioned above , tumor sample analysis showed a high level of PD-L1 and PD-L2 expression at baseline and post-treatment peripheral blood studies in patients show an increase in absolute number of total T cells including CD4, CD8, and natural killer (NK) cells. Nanostring technology has been used to compare gene signatures in pre- and post-treatment samples of peripheral blood in patients to show an upregulation of an interferon (IFN)-gamma-induced signature, T-cell receptor (TCR) signaling, and activation patterns of immune-related genes proving the activated state of the immune system after therapy with a PD-1 antibody. None of these agents are actually directed against the cancer cells. This is a ‘proof of principle’ that the immune system can be modified at a targeted level to induce an effective response against malignancies even when a specific tumor antigen cannot be isolated. The next few years are going to be crucial in determining the full potential of this approach.
Targeted antibody therapies
Combination therapies with targeted antibodies or immune modifiers such as brentuximab vedotin or lenalidomide, respectively are key to the further development of this approach. Well-designed studies on actual tumor tissue complete with the surrounding microenvironment are essential to understanding the mechanism of action as well as resistance to these agents.
Based on clinical experience, it is recognized that most malignancies are associated with a state of immunosuppression and attempts to modify the immune system to influence malignancies date back to 1909 when Paul Ehrlich suggested that the immune system may control cancer [3,4]. Since then there have been two major approaches to modify the immune response against cancer: for instance boosting the innate immunity or eliciting an adaptive response through ‘education and sensitization’ of cytotoxic T cells against tumor antigens, or directly engaging them with monoclonal antibodies against specific proteins on malignant cells. Attempts to modify the cytokine milieu by IFN and interleukin 2 (IL-2) have been used in the treatment of cancers, particularly for the more indolent malignancies such as chronic myeloid leukemia (CML) and indolent lymphomas, while tumor vaccines have been developed to sensitize the immune system to specific tumor antigens with varying degrees of success.
Allogeneic stem cell transplantation
Allogeneic stem cell transplantation remains the most successful form of immunotherapy in hematologic malignancies. Evidence that transplanted allogeneic donor T cells could mount an effective anti-tumor response, for example, a graft-versus-tumor response against cells that had escaped both chemotherapy and radiation, was first demonstrated in 1987 by the use of donor lymphocyte infusions to induce remissions in patients with leukemia who had relapsed after myeloablative conditioning . In 1989, it was demonstrated that graft-versus-host (GvHD) disease was associated with a decreased risk of relapse in patients undergoing an allogeneic stem cell transplant . Responses are durable and cures are possible even with the use of non-myeloablative allogeneic transplants. This is testament to the effectiveness of a strong immune response in many hematologic malignancies albeit at a significant cost of GvHD and morbidity and mortality associated with continued lifelong immunosuppression. The exact mechanisms of this immune response are multifactorial and remain elusive.
Chimeric antigen receptor T-cell therapy
Adoptive therapy by engineered chimeric antigen receptor (CAR) T cells and now CAR-NK cells are attempts to strengthen a host cytotoxic immune response against specific tumor antigens. The clinical response seen with CAR-T cells against anti-CD19-expressing malignancies speaks to the success of this approach. Numerous CARs are now in various stages of development. This requires the recognition and targeting of specific tumor antigens and an appropriate immunological background in order for the infused cells to adequately function. The combination of these technologies with immune checkpoint inhibitors appears to be the most logical next step.
Bi-specific T-cell engager antibody technology
The use of monoclonal antibodies to selectively target specific tumor antigens on tumor cells has been in place since the clinical success of the chimeric monoclonal antibody rituximab, which targets CD20 on B cells. Since then direct targeting of tumor cells with specific antibodies, either alone or as an antibody–drug conjugate or radioimmunoconjugate that delivers radiation or chemotherapy as a payload to targeted tumor cells has proven to be a successful anti-cancer approach. Lately, the use of antibodies to bring a cytotoxic T cell in proximity to a tumor cell using the bi-specific T-cell engager (BiTE) antibody technology is a novel way to engage the immune system in the fight against cancer. Blinatumomab has two antibody-biding sites, a CD3 site for T cells, and a CD19 site for the malignant B cells. On engagement with the tumor cell, the antibody brings the activated T cell in close proximity to the tumor cells resulting in clinical responses that have led to the approval of this agent for Philadelphia chromosome-negative (Ph-negative) acute lymphoblastic leukemia (ALL); this agent is now being evaluated in B-cell malignancies as well. This brings the innate immune system right to the target, allowing a more specific response without antigen sensitivity.
With all this, we can now approach blood cancers armed with an immune response that may result in a more durable clinical benefit, a powerful innate tool that may be more potent than chemotherapy or radiotherapy combined. Seeing a cytotoxic T cell and NK cell in action is impressive with the release of powerful enzymes such as granzyme, perforin, and activation of the apoptotic pathway that would be a challenge for any ‘targeted cancer’ cell to evade. Questions remain on how to harness this potential fully in a personalized manner for individual patients knowing that the immune milieu in any host is an amalgam of the environment, the microbiome, hormonal influences, and other unknowns that are forever changing.
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