Intravenous Immunoglobulin G (IVIg) Suppresses HSP70-1 and Has Potential Therapeutic Effects Against Multiple Myeloma and Lymphoma

Intravenous Immunoglobulin G (IVIg) has been in wide use for over 20 years and is approved for treatment of immune deficiencies, autoimmune disease and acute infections. The ability of IVIg to suppress inflammation would also suggest it has a role to play in suppressing the growth of malignant cells, particularly given the now accepted bidirectional relationship between inflammation and cancer. In several case reports, patients with malignancies such as Kaposi’s sarcoma, thyroid cancer and peripheral nerve sheath tumors experienced remission of their malignancies after receiving IVIg for immune deficiency(Shoenfeld and Krause 2004). Furthermore, a clinical trial in patients with advanced melanoma also reported a therapeutic effect of the anti-inflammatory dose of IVIg of 2 g/Kg (Schachter, Katz et al. 2007). These reports suggest that the pooled IgG of over 10,000 healthy donors is an unrealized and potentially useful anti-cancer agent that may augment both current and new chemotherapy regimens. However, the mechanism of response may not be limited to effects on inflammation or immunity, and might include a direct effect on tumor cells. To address this, we investigated the effect of IVIg on cell lines of non-Hodgkin’s lymphoma and multiple myeloma (MM).

A panel of MM and other cell lines derived from Burkitt’s lymphoma (BL) and mantle cell lymphoma (MCL) were treated with dialyzed IVIg (10 mg/ml), which is in the 1-2 g/Kg anti-inflammatory clinically achievable range. The effects were evaluated both alone or in combination with proteasome inhibitors, bortezomib (BZB) and carfilzomib (CFZ), or the HSP90 inhibitors 17AAG and AUY-922. The efficacy of these drugs have their clinical utility limited due to HSP70-1 induction hence, IVIg makes a good choice for combination therapy.

Treatment with 10 mg/ml IVIg suppressed the growth of all cell lines at 3 days compared to the bovine serum albumin control. This effect was accompanied by a G₁cell cycle arrest and suppression of pro-tumor cytokines including IL-6, IL-8, IL-10 and GM-CSF. The combination of IVIg with BZB or CFZ was synergistic, and IVIg also resensitized BZB-resistant MM cells to BZB. The combination of IVIg and the HSP90 inhibitors 17AAG or AUY-922 was highly synergistic at suppressing the cells growth. IVIg strongly suppressed the expression of HSP70-1 both alone and when induced by HSP90 inhibitors. Varying the sequence of administration revealed that pretreatment with IVIg for 24 hours was superior in growth suppression compared to simultaneous administration of IVIg with 17AAG or AUY922 or pretreatment with 17AAG or AUY-922. IVIg treatment also suppressed expression of mutant p53, for which HSP70-1 serves as a cochaperone.

IVIg has a potent ability to suppress MM, MCL and BL cell growth, through a mechanism that may involve its suppression of HSP70-1 expression. We hypothesize that IVIg contains IgG against HSP70-1, which results in enhanced HSP70-1 turnover and blocks the heat shock response induced by proteasome and HSP90 inhibitors. This mechanism would raise the possibility that IVIg could enhance the efficacy of targeted inhibitors, and inhibit mechanisms used by malignancies to evade these agents. Given its long clinical experience and exceptional safety profile, IVIg could be rapidly incorporated into the treatment of hematological malignancies.

References

Schachter, J., U. Katz, et al. (2007). “Efficacy and safety of intravenous immunoglobulin in patients with metastatic melanoma.” Annals of the New York Academy of Sciences 1110: 305-314.

Shoenfeld, Y. and I. Krause (2004). “i.v.IG for autoimmune, fibrosis, and malignant conditions: our experience with 200 patients.” Journal of clinical immunology 24(2): 107-114.

Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees.