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Review
. 2024 Feb 5;20(12):1021-1034.
doi: 10.20892/j.issn.2095-3941.2023.0222.

Azoximer bromide and hydroxyapatite: promising immune adjuvants in cancer

Jean-François Rossi  1   2 , Patrick Frayssinet  3 , Maksim Matciyak  4 , Nikolai Tupitsyn  5
Affiliations
Review

Azoximer bromide and hydroxyapatite: promising immune adjuvants in cancer

Jean-François Rossi et al. Cancer Biol Med. .

Abstract

Immune adjuvants are immune modulators that have been developed in the context of infectious vaccinations. There is currently a growing interest in immune adjuvants due to the development of immunotherapy against cancers. Immune adjuvant mechanisms of action are focused on the initiation and amplification of the inflammatory response leading to the innate immune response, followed by the adaptive immune response. The main activity lies in the support of antigen presentation and the maturation and functions of dendritic cells. Most immune adjuvants are associated with a vaccine or incorporated into the new generation of mRNA vaccines. Few immune adjuvants are used as drugs. Hydroxyapatite (HA) ceramics and azoximer bromide (AZB) are overlooked molecules that were used in early clinical trials, which demonstrated clinical efficacy and excellent tolerance profiles. HA combined in an autologous vaccine was previously developed in the veterinary field for use in canine spontaneous lymphomas. AZB, an original immune modulator derived from a class of heterochain aliphatic polyamines that is licensed in Russia, the Commonwealth of Independent States, and Slovakia for infectious and inflammatory diseases, is and now being developed for use in cancer with promising results. These two immune adjuvants can be combined in various immunotherapy strategies.

Keywords: Immune adjuvants; Toll receptor agonists; azoximer bromide; cancer; hydroxyapatite; immunotherapy.

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Conflict of interest statement

Drs. JF Rossi and N Tupitsyn reported receiving investigator-initiated and collaborative grants from Petrovax NPO Pharm. M Matciyak is employed by Petrovax NPO Pharm. Dr. Patrick Frayssinet is a co-founder of HASTIM Inc.

Figures

Figure 1
Figure 1
Dynamics of the inflammatory/immune response. 1. After infection or injury, different signals, such as damage-associated molecular patterns (DAMPs) or pathogen-associated molecular patterns (PAMPs), are detected by different receptors, including pathogen recognition receptors (PRRs). 2. This initiation step leads to the activation of numerous cells involved in the start of the inflammatory response, such as neutrophils (N), monocytes (Mo), macrophages (M1), natural killer cells (NK), and Langherhans cell-like dendritic cells (LC/DC), with production of chemokines [chemokine C-X-C motif ligand (CXCL)], interleukins (IL), tumor necrosis factor (TNF), and monocyte chemoattractant protein-1 (MCP-1). 3. After the initiation step, the appropriate immune response takes place at the level of the draining lymph node with the process of antigen presentation and the differentiation of dendritic cells (DC) allowing the specific immune response (cellular and humoral). 4. The initial inflammatory response is rapidly balanced by immune suppression and repair and mainly mediated by transforming growth factor (TGF)-β and IL-10.
Figure 2
Figure 2
Tumor microenvironment and potential activities of immune adjuvants. The tumor microenvironment combines immune cells, which facilitate escape from immune surveillance, and cells that can eliminate cancer cells due to cytotoxic activities. Generally, the balance goes in the direction of tumor progression and the role of an immune adjuvant helps reverse this negative balance. Immune effector cells (IECs) to control cancer cells include dendritic cells (DC), CD4, cytotoxic CD8, natural killer (NK), NKT, γδ T-cells, B- and plasma cells (BPC), and chimeric antigen receptor (CAR) T-cell used therapeutically. IECs that promote cancer cell growth include subpopulations of CD4, CD8, NK, and myeloid suppressive cells (MSC). Several factors influence the tumor microenvironment, including the state of the immune system, cytokines, and chemokines, which are secreted by IEC, such as interleukin (IL) or interferon (IF) gamma (g). The microbiota can be present in the microenvironment as in gastrointestinal cancers or indirectly influences the IECs.
Figure 3
Figure 3
An 84-year-old man with cholangiosarcoma treated with only autologous serum vaccine (APAVAC®), A: CT-scan and FDG pet-scan before treatment and B: evaluation after 4 doses of sub cutaneous injection of APAVAC® once per week.
Figure 4
Figure 4
A 70-year-old patient with hepatocarcinoma treated by APAVAC®, A: before treatment and B: after 3 months of therapy, once per week for 4 injections followed by once monthly with a partial response.
Figure 5
Figure 5
Dynamics of cellular and humoral immunity parameters in patients with mild infection (group I) and severe course (group II) of community-acquired pneumonia before and after treatment, including polyoxidonium. On day 10, circulating CD3+ lymphocytes were significantly increased (P < 0.05), rising from 48.47% ± 2.43% to 73.16% ± 2.43% in group I and from 48.70% ± 2.65% to 61.47% ± 3.09% in group II. CD4+ lymphocytes were also significantly increased (P < 0.05) from 31.56% ± 1.30 to 45.56% ± 1.59% in group I and from 31.29% ± 1.78% to 41.29% ± 1.82%. CD8+ lymphocytes were significantly increased (P < 0.05) from 17.44% ± 0.03% to 25.44% ± 0.03% in group I and from 17.50% ± 1.92% to 20.01% ± 0.92%. No changes were observed for CD19+ lymphocytes,.
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