IDO Inhibitors May Augment Immunotherapy in NSCLC

Alex A. Adjei, MD, PhD, FACP

Combination therapies with agents such as indoleamine 2,3-dioxygenase (IDO) inhibitors may have the potential to synergize with immunotherapeutic approaches to improve immune function against tumor cells.

The concept of immunotherapy, or using the body’s immune system to selectively target tumor cells, is not new, but it has become a more viable and practical option in cancer treatment over the last decade.^1-3Using antibody-based inhibitors of key immunoregulatory checkpoints—such as cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death receptor-1 (PD-1), and its ligand, PD-L1—durable responses have been observed in advanced, metastatic cancers for which no therapy had previously been available.^4,5

The rationale of these now-proven immunotherapies is that by augmenting any existing antitumor immune response, and at the same time curtailing tumor-based immune-evasion mechanisms (eg, overexpression of PD-L1 in the tumor microenvironment), a much more effective and durable immune response (with the possible added benefits of T-cell memory) can be mounted against the tumor.^1-3

Non-small cell lung cancer (NSCLC) is among the many tumor types in phase III investigation with immunotherapies such as anti-CTLA-4 (ipilimumab) and anti-PD-1/PD-L1 (nivolumab, pembrolizumab).^6-8In addition to antibody-based immunotherapies, the immunoregulatory properties of IDO, an enzyme that plays an integral role in the metabolism of the amino acid tryptophan, has also been recognized as a potential means of promoting tumor-induced tolerance.^2,3The metabolism of tryptophan by IDO appears to function as a critical negative feedback mechanism to prevent uncontrolled cytotoxic immune reactions; overexpression of IDO therefore constitutes a mechanism whereby tumor cells can create a tolerogenic milieu and evade detection and killing by the immune system.²

The immunosuppressive prowess of IDO production was illustrated in an elegant experimental study by Swanson et al, which showed that the production of IDO in the lung by interstitial antigen presenting cells (iAPCs) is an effective suppressor of T-cell responses both in vitro and in vivo.^9,10This suppressive effect of iAPC-produced IDO appears to play an important homeostatic role by preventing unnecessary T-cell activation and inflammation in the lungs, which are constantly exposed to inhaled exogenous antigens.⁹

Conversely, however, this same physiologic process has the potential to result in inappropriate immune suppression if co-opted by tumors. Indeed, in experimental models, the overexpression of IDO before transplantation effectively suppressed acute rejection of haplo-mismatched lung allografts in the absence of exogenous immunosuppression.⁹

In his recent presentation at the 12th Annual International Congress on Targeted Therapies in Cancer®, Alex A. Adjei, MD, PhD, professor and chair of the department of medicine, and Katherine Anne Gioia Chair in Cancer Medicine at the Roswell Park Cancer Institute in Buffalo, New York, pointed to evidence for expression of IDO1—the gene that encodes the IDO enzyme—in the microenvironment of many different cancers, including colon and breast, and its association with decreased survival.10 He also noted that, in preclinical models, inhibition of IDO1 reduced tumor growth, augmented antitumor immune responses, and has the potential to synergize with cytotoxic therapies, tumor vaccines, and other immunotherapies.¹⁰

Accordingly, several inhibitors of IDO, such as 1-methyl-DL-tryptophan (1-MT), have been developed, and are now under investigation for the treatment of various cancers, including NSCLC.¹⁰

In a phase I, dose-escalation study of patients (N = 52) with advanced cancers, the safety and efficacy of the IDO1 inhibitor INCB024360 were examined.¹¹The treatment was generally well tolerated at doses of up to 700 mg twice a day, and toxicity was not dose related; abdominal pain, hypokalemia, and fatigue were the most common grade 3 or 4 adverse events (AEs), each occurring in 9.6% of patients. After 56 days, stable disease (SD) was seen in 15 patients, and 7 patients had SD lasting 112 days or longer.¹¹

Pharmacodynamic effects of this IDO inhibitor could also be observed in the study, with doses of 300 mg twice a day or greater resulting in more than 90% inhibition of IDO1.

Grace K. Dy, MD

Thus, the development of IDO inhibitors has the potential to introduce yet another targetable pathway for the treatment of advanced NSCLC. Commenting on the differences between IDO inhibitors and other targeted therapies in NSCLC, Grace K. Dy, associate professor of oncology in the department of medicine at Roswell Park Cancer Institute, said, “Instead of targeting specific mutated proteins derived from oncogenes, IDO inhibitors are small molecules that can potentially augment the response to immunotherapies, by inhibiting the enzyme IDO.”

Dy explained that IDO was initially identified in the placenta as an immunosuppressive mechanism for the fetus to escape rejection by the maternal immune system, and that, subsequently, IDO was found to be highly expressed in various malignancies.

“This is thought to be one of the mechanisms tumors use to evade immune surveillance, by depleting tryptophan, and causing accumulation of catabolites, which in turn abrogates T-cell function and viability. IDO inhibitors thus have potential for broad applicability across genetically diverse cancer populations,” Dy said.

Clinical Pearls

• Combination therapies with IDO inhibitors may have the potential to synergize with immunotherapeutic approaches to improve immune function against tumor cells.
• Overexpression of IDO constitutes a mechanism whereby tumor cells can create a tolerogenic milieu and evade detection and killing by the immune system.
• Inhibition of IDO1 reduced tumor growth and augmented antitumor immune responses in preclinical models, and has the potential to synergize with cytotoxic therapies, tumor vaccines, and other immunotherapies.
• Development of IDO inhibitors has the potential to introduce another targetable pathway for the treatment of advanced NSCLC.
• The KEYNOTE 037 trial is investigating pembrolizumab with an IDO inhibitor in a 2-part phase I/II study designed to assess the efficacy and safety of pembrolizumab (MK-3475) in combination with an IDO inhibitor (INCB024360) in patients with advanced solid tumors (phase I part of the study), and subsequently evaluate this combination in patients with advanced NSCLC (phase II portion of the trial).

The use of IDO inhibitors as combination therapy also has the potential to further augment responses to existing immunotherapies already under investigation in NSCLC, such as anti-PD-1 agents. In this regard, the KEYNOTE 037 trial is investigating the combination of pembrolizumab (an anti-PD-1 agent) with an IDO inhibitor in a 2-part phase I/II study.¹²This trial is designed to initially assess the efficacy and safety of pembrolizumab (MK-3475) in combination with an IDO inhibitor (INCB024360) in patients with advanced solid tumors (phase I part of the study), and subsequently, to evaluate this combination in a randomized, double-blinded, placebo-controlled manner in patients with advanced NSCLC (phase II portion of the trial).

Different doses of the IDO inhibitor (in combination with pembrolizumab) will be evaluated in the phase I portion (in various tumor types) to determine the dose for further evaluation, while the phase II portion will include only patients with NSCLC (defined as histologically or cytologically stage 3b, 4, or recurrent NSCLC) and will assess the antitumor efficacy of this combination. The phase II portion will have the primary outcome measure of progression-free survival (PFS), with secondary endpoints of overall response rate and durability of response, as well as AEs.

Commenting on the rationale for the KEYNOTE 037 trial, Dy said: “Not all patients derive benefit from single-drug immunotherapies, as there are multiple ways cancers can circumvent T-cell responses. Combination therapies, such as with IDO inhibitors, have the potential to synergize with immunotherapeutic approaches.” Completion of the study is anticipated for November 2017.

References

1. Aldrich JF, Lowe DB, Shearer MH, Winn RE, Jumper CA, Kennedy RC. Vaccines and immunotherapeutics for the treatment of malignant disease.Clin Dev Immunol. 2010;2010:697158.
2. Soliman H, Mediavilla-Varela M, Antonia S. Indoleamine 2,3-dioxygenase: is it an immune suppressor?Cancer J. 2010;16(4):354-359.
3. Munn DH. Blocking IDO activity to enhance anti-tumor immunity.Front Biosci(Elite Ed). 2012;4:734-745.
4. Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma.N Engl J Med. 2010;363(8):711-723.
5. Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer.N Engl J Med. 2012;366(26):2443-2454.
6. Clinicaltrials.gov: Phase 3 Trial in Squamous Non-Small Cell Lung Cancer Subjects Comparing Ipilimumab Plus Paclitaxel and Carboplatin Versus Placebo Plus Paclitaxel and Carboplatin. NCT02279732.
7. Clinicaltrials.gov: Study of BMS-936558 (Nivolumab) Compared to Docetaxel in Previously Treated Advanced or Metastatic Squamous Cell Non-small Cell Lung Cancer (NSCLC) (CheckMate 017). NCT01642004.
8. Clinicaltrials.gov: Study of Pembrolizumab (MK-3475) Compared to Platinum-Based Chemotherapies in Participants With Metastatic Non-small Cell Lung Cancer (MK-3475-024/KEYNOTE-024) NCT02142738.
9. Swanson KA, Zheng Y, Heidler KM, Mizobuchi T, Wilkes DS. CDllc+ cells modulate pulmonary immune responses by production of indoleamine 2,3-dioxygenase.Am J Respir Cell Mol Biol. 2004;30(3):311-318.
10. Adjei AA. Emerging Targets in Lung Cancer. Available at: http://e-syllabus.gotoper.com/_media/_pdf/ITT14_1011_0930_Adjei_EmergingTargets_FINAL.pdf. Accessed November 5, 2014.
11. Beatty GL, O’Dwyer PJ, Clark J, et al. Phase I study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the oral inhibitor of indoleamine 2,3-dioxygenase (IDO1) INCB024360 in patients (pts) with advanced malignancies.J Clin Oncol. 2013;31(suppl): Abstract 3025.
12. Clinicaltrials.gov: A Phase 1/2 Study Exploring the Safety, Tolerability, and Efficacy of MK-3475 in Combination With INCB024360 in Subjects With Selected Solid Tumors and Advanced NSCLC (INCB 24360 202 / MK-3475-037 / KEYNOTE-037). NCT02178722.