Targeting resistance to immune checkpoint inhibitors with INB03

Tremendous progress has been made in the treatment of cancer over the last 50 years, but much work remains. The biggest change in the last decade has been the rise of immunotherapy for cancer. Clinicians now realize one of the most potent tools in their therapeutic tool box is the patient’s immune system. Currently approved immunotherapies do not work for everyone. A major goal of the medical community is to reduce the number of patients resistant to immunotherapy.

Treatment of melanoma was the proving ground for checkpoint inhibitor therapy (CPI) and remains the most studied cancer for which CPI is indicated. In previously untreated patients with metastatic melanoma, a response rate as high as 72% can be obtained in some patients.¹ Unfortunately, this impressive response is not always long-lived. Secondary resistance to CPI develops in many people who achieved an initial objective response to CPI after only two years.² Once relapse occurs, the chances for successful treatment dim.

One strategy to reverse primary or secondary resistance to CPI is to add a second immunotherapy to CPIs that targets the cause of the resistance. Combination therapy ideally mixes drugs that have synergy so the response of the tumor is greater than the response of either therapy alone (monotherapy). INmune Bio plans to explore the possibility of combining INB03 with CPI, in patients who are CPI resistant, in clinical trials. INB03 is a second-generation selective, dominant-negative, inhibitor of soluble tumor necrosis factor (sTNF), that precisely neutralizes sTNF without affecting trans-membrane TNF.   In mouse models of fibrosarcoma, neutralizing sTNF with INB03 resulted in fewer and smaller tumors with improved survival. These effects were caused by a reduction in the number and function of myeloid derived suppressor cells (MDSC), improved NK/DC cross-talk (natural killer and dendritic cells respectively), and improved recruitment of CD8 positive cytotoxic T cells to the tumor.³ Arguably, the most important effects are on myeloid derived suppressor cells (MDSC).

MDSC may be the most important cell you’ve never heard of!⁴ Many cancer patients have MDSC in blood or the tumor. MDSC develop from normal myeloid cells exposed to sTNF produced by the cancer as part of the chronic inflammation associated with progressive disease. The number of MDSC in the blood and/or tumor predict the severity of the cancer and prognosis. The more MDSC, the worse the prognosis. Circulating MDSC are predictive of the failure of CPI in melanoma.⁵ Experts agree that eliminating MDSC in the patient should improve the response of the patient to immunotherapy. This is the strategy at INmune Bio. INmune Bio plans to use circulating MDSC as a biomarker to identify patients who will benefit from INB03 therapy. The company plans to treat patients who are resistant to CPI monotherapy with combination therapy. INmune Bio believes treatment with INB03 will decrease the MDSC in the tumor microenvironment (TME) to allow the CPI to work.

When MDSC are eliminated, you take the brakes off the immune system. CPIs are much more effective in “hot tumors”, with immune effector cells infiltrate. INmune Bio believes that addition of INB03 will allow cytotoxic cells to infiltrate the tumor and allow the CPIs to work and hopefully eliminate the cancer. INmune Bio is in the first step of a multi-step process to testing combination therapy of INB03 with CPI. The design of the Phase II combination therapy trial will enroll patients resistant to CPI with biomarkers of inflammation including elevated MDSC. The goal of the trail is to reverse resistance to CPI in these unfortunate patients. An open label dose escalation Phase I trial of INB03 in patients with advanced solid tumors is ongoing. INmune Bio hopes to attract industry partners to provide CPI for this novel trial.

The tools to improve cancer care are in hand, but those tools must be deployed wisely. Careful use of biomarkers to match therapy with the biology of the patient’s tumor and immune system are needed to make progress. Reversing immunologic resistance mechanisms to allow immunotherapy to work better is a new treatment paradigm ideally used early in the patient journey. Thoughtful, data-driven therapeutic decision-making should make a difference at the bedside. The future is bright.

To learn more, visit inmunebio.com.

References
¹Larkin, J., et al. N Engl J Med. 2015;373:23-34.
²Syn, N.L., et al. Lancet Oncol. 2017;18:e731-e741
³Sobo-Vujanovic, A., et al. Cancer Immunol Res. 2016;4:441-451.
⁴Tesi, R.J. Trends Pharmacol Sci. 2019;40:4-7.
⁵Meyer, C., et al. Cancer Immunol Immunother. 2014;63:247-257.