Immune precision medicine for cancer: a novel insight based on the efficiency of immune effector cells

Abstract

Cancer cell growth is associated with immune surveillance failure. Nowadays, restoring the desired immune response against cancer cells remains a major therapeutic strategy. Due to the recent advances in biological knowledge, efficient therapeutic tools have been developed to support the best bio-clinical approaches for immune precision therapy. One of the most important successes in immune therapy is represented by the applicational use of monoclonal antibodies, particularly the use of rituximab for B-cell lymphoproliferative disorders. More recently, other monoclonal antibodies have been developed, to inhibit immune checkpoints within the tumor microenvironment that limit immune suppression, or to enhance some immune functions with immune adjuvants through different targets such as Toll-receptor agonists. The aim is to inhibit cancer proliferation by the diminishing/elimination of cancer residual cells and clinically improving the response duration with no or few adverse effects. This effect is supported by enhancing the number, functions, and activity of the immune effector cells, including the natural killer (NK) lymphocytes, NKT-lymphocytes, γδ T-lymphocytes, cytotoxic T-lymphocytes, directly or indirectly through vaccines particularly with neoantigens, and by lowering the functions of the immune suppressive cells. Beyond these new therapeutics and their personalized usage, new considerations have to be taken into account, such as epigenetic regulation particularly from microbiota, evaluation of transversal functions, particularly cellular metabolism, and consideration to the clinical consequences at the body level. The aim of this review is to discuss some practical aspects of immune therapy, giving to clinicians the concept of immune effector cells balancing between control and tolerance. Immunological precision medicine is a combination of modern biological knowledge and clinical therapeutic decisions in a global vision of the patient.

Keywords: Cancer; Dendritic cells; Immunotherapy; NK lymphocytes; Precision therapy; T-lymphocytes; Vaccination.

Fig. 1

Results of the phase II study combining in vivo γδ T-cells stimulator (IPH1101), interleukin 2 and rituximab for patients having follicular lymphoma. The patients were treated with bromohydrin pyrophosphate (BrHPP, Innate Pharma Inc. Marseille, France, at 750 mL/m², 3 times every 3 weeks), low dose IL-2 (8 MIU, daily for 5 days, every 3 weeks) and rituximab (375 mg/m², 4 times weekly). There was a dramatic increase of circulating T-lymphocytes without any amplification of other lymphocyte subpopulations including Tregs. a The change of circulating immune cell subpopulations at day 21 as compared to day 0. b Complete response rate (CRR) and objective response rate (ORR) in patients having FL depending on the FLIPI (Follicular Lymphoma International Prognostic Index), i.e., low index and intermediate/poor index. IL2: interleukin 2; Treg: T-regulator; NK: natural killer lymphocytes; C1D8: cycle 1 Day 8

Fig. 2

Ex vivo maturation and differentiation of dendritic cells (DC) from monocytes. Mononuclear cells were collected by apheresis from the patient. These mononuclear cells were differentiated ex vivo to immature DC in the presence of GM-CSF and IL4 or IL13. The mature DCs were obtained after stimulation by TNF-α and they exhibited different biomarkers, such as CD86, CD80, CCR7, and the antigen-MHC complex. GM-CSF: Granulocyte–Macrophage Colony Stimulating Factor; IL: interleukin; TNF: Tumor Necrosis Factor; MHC: major histocompatibility complex; CTL: cytotoxic lymphocytes; CCR: C–C chemokine receptor; Ag: antigen; α_v: integrin alpha V; β5: integrin beta 5; CTL: cytotoxic lymphocytes; DC: dendritic cells; FcR: Fc receptor; Poly-IC: polycytidylic acid; RNA: ribonucleic acid

Fig. 3

A phase II clinical trial with DC pulsed with tumoral cell lysates from patients having follicular lymphoma. a Intradermal injection of 0.2 mL of DC-pulsed with tumoral lysates (5 × 10⁶ DC/mL) (5 sites) and KLH intradermal injection (100 µg in 0.2 mL) used as a control. Magnification: ×1; b Delayed hypersensitivity after intradermal injections (1) and cutaneous biopsies (2) showing important CD3 positive infiltrate and CD68 positive macrophages; c [18F] fluorodeoxyglucose-positron emission tomography scanning (FDG pet-scan): (1) before vaccination with tumoral lymph node (yellow arrow), (2) 15 days after the vaccination with increased hypermetabolism of the lymph node (white arrow), (3) 2 months after the vaccination with the disappearance of the hypermetabolism (yellow arrow), suggesting an activation of the IECs within the lymph node. 1: injection site with 0.2 mL of DC-pulsed with tumoral lysates; 2: injection site of control; DC: dendritic cells; KLH: Keyhole limpet hemocyanin

Fig. 4

Delayed complete response observed in a patient receiving GM-CSF and rituximab, suggesting an in vivo vaccination. A 58 years-old Male was diagnosed in December 1996 as follicular lymphoma grade II, stage IIIAb, FLIPI 2 with high tumor burden. He received mini-CHOP and interferon alfa followed by a partial response. His disease progressed in March 1998 and he was treated by three courses of DHAP and high dose therapy with autologous transplantation associated with a complete response. He relapsed in May 1999 and received rituximab with partial response. After reprogression in May 2000 (a), he received GM-CSF and rituximab with a long-lasting regression and fluctuation of the tumor over 2 years, as observed on the following scanners (b–d) and no tumor on e, suggesting an in vivo vaccination. He reprogressed in October 2006 and was treated by rituximab with stabilization for 1 year. FLIPI: Follicular Lymphoma International Prognostic Index; CHOP: cyclophosphamide, doxorubicin, vincristine, prednisone; DHAP: dexamethasone, cytarabine, cis-platinum; GM-CSF: Granulocyte–Macrophage Colony Stimulating Factor

Fig. 5

Illustration of the immune checkpoint molecules and their inhibitors. Immune checkpoint inhibitors are potent molecules implicated in the cell–cell communications. They are present on T-cells and their ligands are shared by tumor cells and dendritic cells (DC). Immune checkpoint molecules send negative signals to T cells and inhibit the later activities. Monoclonal antibodies have been developed against different molecules and used as therapeutic checkpoint inhibitors. CTLA-4: cytotoxic T-lymphocyte antigen-4, TcR: T cell receptor; MHC: major histocompatibility complex; HVEM: Herpes Virus Entry Mediator; PD1: programmed death; PDL-1/2: programmed death ligand-1/2; Lag-3: lymphocyte-activation gene 3; BTLA: B- and T-lymphocyte attenuator; Ag: antigen

Fig. 6

Time-windows of opportunity in immune therapy for cancers. After tumor mass reduction by chemotherapy, there is a burst of cytokines and lymphodepletion that are benefitting for in vivo activity of the immune effector cells such as NK or γδ T-lymphocytes. CAR-T cells are engineered cytotoxic T-cells that could be used instead of chemotherapy when chemoresistance is observed or to complete tumor cell killing. To control residual disease, repetitive administration of immune effector cells could be proposed. Immune checkpoint inhibitors are potent immune adjuvants to be combined for amplifying the T-cell response, probably at a lower dose and to avoid immune exhaustion. The role of vaccine using neoantigens is probably an alternative therapy for frail patients and this represents a good opportunity to challenge the immune specific functions along with the immune control of the tumor. IEC: immune effector cells; CAR-T: chimeric antigen receptor T-cell therapy; MRD: minimal residual disease; PR: partial response, CR: complete response