IO. beyond checkpoint inhibitors
June 12, 2019
immuno-oncology has created a paradigm shift in the treatment of some advanced-stage cancers often where no treatment was available or effective. while it has provided significant advances in treatment, checkpoint inhibitors are not always effective. and a significant proportion of patients that receive these treatments do not develop therapeutic responses, highlighting the need for more effective therapies. while immunotherapy continues to be a major focus if research in oncology today, a greater understanding of a tumour’s interactions with its microenvironment and the immune system is guiding this research. a key goal now is to develop a deeper understanding of why some patients respond to IO therapies while others exhibit resistance, or become refractoryresistance] to IO therapy with time.
knowledge of these interactions between the tumour and the immune system is creating many new therapeutic opportunities. and some, though still few, of the therapies under development are truly individualized for the patient, ushering in a new, even more tailored approach to personalized medicine.
mAbs are often the standard of care in many metastatic cancers- some mAbs trigger the immune system to attack and kill cancer cells[think trastuzumab] and others work by acting on cells of the immune system like CTLA-4 and PD-1 | PD-L1 [checkpoint inhibitors like ipilimumab, nivolumab and pembrolizumab].
we’ve all heard about monoclonal antibodies[mAbs]but what about GITR, BITE and OX40- are you familiar.
the current drug discovery pipeline is rich beyond checkpoint inhibitors.
agonistic monoclonal antibodies [ agonistic mAbs] or stimulatory checkpoint pathways
agonistic mAbs offer a new therapeutic option which has the potential to generate anticancer immunity by various mechanisms- agonistic mAbs are fundamentally different from mAbs which block negative immune checkpoint such as anti-CTLA-4 or anti-PD-1
tumor necrosis factor receptors [TNFRs]
targeting co-stimulatory members of the tumour necrosis factor receptor [TNFR] family with agonist mAbs enhances t cell function, which has led to encouraging therapeutic results in cancer-bearing hosts – TNFRs include glucocorticoid-induced TNFR [GITR; CD357], CD27, OX40 [CD134], and 4-1BB [CD137], inducible T-cell costimulatory [ICOS], 4-1BB, CD40.
adoptive cell therapy [ACT]
using this approach, tumor-specific cytotoxic t cells are infused into cancer patients with the goal of recognizing, targeting, and destroying tumour cells. adoptive cell therapy creates rather than unleashes a productive immune response. and include chimeric antigen receptor therapy [CAR] and tumour infiltrating lymphocytes [TILs].
antibody drug conjugates [ADC]
antibody drug conjugates [ADCs] are monoclonal antibodies [mAbs] attached to biologically active drugs by chemical linkers. by combining the unique targeting of mAbs with the cancer-killing ability of cytotoxic drugs, ADCs allow sensitive discrimination between healthy and diseased tissue.
bispecific t-cell engagers [BiTE]
this new immunotherapy strategy refers to bispecific antibodies that bind to two different antigens with high affinity. bispecific t-cell engagers [BiTE] are a particular type of bispecific antibodies that bind to CD3+ cells and to a tumour specific antigen. the first BiTE to be approved by the FDA was blinatumomab for B-cell acute lymphoblastic leukemia [B-ALL]. blinatumomab binds to CD3, expressed by T cells, and to CD19, expressed by B cells.
oncolytic viruses [OV]
oncolytic viruses, like vaccines, stimulate antigen presentation and generate an anti-tumour response. oncolytic viruses infect | invade, replicate within and kill tumour cells, inducing antigen release and promoting a pro-inflammatory environment.
the only FDA approved oncolytic virus is the T-VEC [talimogenelaherparepvec], consisting of attenuated herpes simplex virus [HSV]
the goal of cancer vaccination is to induce an efficient antigen presentation generating an anti-tumour response, based on CD4+ and CD8+ T lymphocytes against tumour- specific antigens, that is sufficiently robust to be able to produce long-lasting clinical responses. sipuleucel-T is the only cancer vaccine approved by the FDA. this vaccine consists of autologous peripheral blood mononuclear cells [PBMC].
molecules targeting tumour microenvironmen
indoleamine-pyrrole 2,3-dioxygenase [IDO]
IDOs [IDO1 and IDO2] are tryptophan catabolic enzymes that catalyze the conversion of tryptophan into kynurenine. the depletion of tryptophan and the increase in kynurenine exert important immunosuppressive functions by activating t regulatory cells and myeloid-derived suppressor cells, suppressing the functions of effector t and natural killer cells, and promoting neovascularization of solid tumours. its known that a second signal is needed to activate IDO1 inhibited t cells – perhaps checkpoint inhibitors don’t actually fit the bill. all current clinical strategies, however, focused on combination with anti-PD-1, PD-L1, or anti-CTLA-4 agents.
toll like receptors [TLR]
TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways.
next generation check point inhibitors
TIGIT is an immunomodulatory receptor that may play a role in the suppression of T-cell production and activation. TIGIT is also involved in tumor cell immune evasion and the inhibition of antiviral immune responses. Anti-TIGIT antibodies are designed to target TIGIT in order to enhance the T-cell–mediated response.
TIM-3 is a marker of exhausted CD8+ t cells. It is highly expressed on CD8 t cells in multiple tumours including melanoma and NSCLC. TIM-3 negatively regulates t-cell activation on CD8 t cells. recent work suggests that TIM-3 also impacts t-cell activation indirectly by acting on other cells in the tumour microenvironment including dendritic cells. Preclinically, TIM-3 blockade has resulted in increased proliferation and cytokine production by CD8 t cells.
B7-H3 is a member of the B7 family of molecules involved in immune regulation and is overexpressed on a wide variety of solid tumour types, especially melanoma and cancers of the head and neck, bladder, and lung. its overexpression is associated with adverse outcomes, and its expression may inversely correlate with responsiveness to anti–PD-1 therapy.
lymphocyte activation gene 3 [LAG-3] is a cell-surface molecule that plays a role in downregulating the immune response. LAG-3 is widely expressed on tumour-infiltrating lymphocytes and cytotoxic t cells.
while PARP inhibitors do not fall under the io umbrella, a recent study by the institute of cancer research [ICR] has found that these precision cancer drugs could unmask certain types of cancers and boost the effectiveness of immunotherapies.
other strategies include the combination of checkpoint inhibitors [CTLA-4 and PD-1 | PD-L1] in combination with other classic therapeutic options including chemotherapy and radiation and in combination with tyrosine kinase inhibitors [TKIs].