Hyperprogression under immunotherapy and mTOR (hypothesis)

Mikhail V. Blagosklonny

Abstract:

Immunotherapy involving Immune Checkpoint Inhibitors can cause rapid tumor growth, particularly in patients with MDM2 amplification. MDM2 and mTOR inhibitors may mitigate this and improve therapy outcomes. Importantly, MDM2 inhibitors block mTOR in cancer cells. As MDM2 inhibitors aren’t approved for human use, mTOR inhibitors like rapamycin and everolimus could be alternatives.

Introduction

The Nobel-prize-winning treatment, Immunotherapy with Immune Checkpoint Inhibitors (ICI), can accelerate tumor growth in a considerable subset of patients, with rates varying between 4% and 29% across various cancer types [1]. According to a meta-analysis, immunotherapy induces hyperprogression (accelerated growth) in 6%-43% of cases [2].

MDM2 amplification is a biomarker of Hyperprogression [3] [1] [4]. MDM2 is a negative regulator of the p53 tumor suppressor.

Patients with MDM2 experience poor clinical outcomes and a substantially increased rate of tumor growth following treatment with single-agent checkpoint (PD-1/PD-L1) inhibitors. Some patients showed a drastic acceleration in progression pace, up to 42.3-fold compared to the period two months prior to immunotherapy [1]. I was diagnosed with lung cancer with multiple brain metastases in January 2023. Regrettably, my lung cancer cells show MDM2 overexpression. Immunotherapy is counter indicated for me.

Progression after Flu vaccination (subjective opinion) 

After my flu shot on Dec 12, 2022, I experienced speech difficulties (dysarthria), suspected as a vaccine side effect, which later escalated into Beal’s palsy. Started four days after vaccination, neurological abnormalities rapidly progressed. An MRI on Jan 12, 2023, found multiple brain lesions resembling infections rather than metastases. Yet, a subsequent brain biopsy revealed them to be metastases from lung cancer. Crucially, my cancer cells exhibit MDM2 amplification.

I self-administered a single dose of rapamycin immediately after MRI and later started receiving dexamethasone along with an MET inhibitor. Tumor biopsy revealed driver MET mutation, METex14, and started on February 4 caused excellent therapeutic response. Notably, a second MRI taken just before I started the MET inhibitor showed no progression while I was only on rapamycin and dexamethasone. I hypothesize that the flu vaccine might have triggered inflammation, simulating a rudimentary form of immunotherapy. This could have induced clinical hyperprogression in cancer with MDM2 amplification. It’s my belief that the anti-inflammatory drugs, rapamycin, and dexamethasone, potentially slowed down this hyperprogression. This is consistent with studies indicating that inflammation and SASP can stimulate cancer growth. 

I’m led to believe that immunotherapy may not be suitable for my MDM2-positive cancer. Yet, I wonder, could rapamycin mitigate hyperprogression and minimize the side effects of immunotherapy?

Rapamycin mitigate hyperprogression, progression and side effects of immunotherapy  

Immunotherapy treatments can lead to severe immune-related adverse events. Sirolimus (rapamycin) improves the efficacy of immunotherapy and eliminates gastrointestinal adverse effects through mTOR inhibition [5]. Combined treatment with sirolimus and anti-PD-1 effectively inhibits tumor growth in mice by inducing the immunogenic death of tumor cells, while simultaneously reducing adverse effects [5].

Several preclinical studies have demonstrated the benefits of combining mTOR inhibitors with immunotherapies [6, 7].

Evidence suggests that rapamycin could enhance immunotherapy in humans [8]. In particular, organ transplant patients, who may also be contending with cancer, can benefit from immunotherapy. Rapamycin, an immunosuppressant, is commonly used in these patients. Notably, those treated with rapamycin show improved outcomes from immune checkpoint blockade cancer therapies [8].

Mdm2 inhibitor mitigate hyperprogression and potentiates immunotherapy of cancer

Overexpression of Mdm2 may lead to hyperprogression, thus, one may suggest that Mdm2 inhibitors could mitigate this process. Indeed, targeting MDM2 in tumors with MDM2 overexpression or amplification helps to overcome hyperprogression in the context of immune checkpoint therapy [9].

MDM2 inhibitor synergizes with PD-1 blockade through enhancing antitumor immunity in the tumor microenvironment.

MDM2 inhibitor synergizes with PD-1 blockade. Notably, MDM2 inhibitor promotes antitumor activity irrespective of the p53 status of the tumors [10]. Thus, MDM2 inhibitors may operate not only through wt p53 activation.

How may we explain that Mdm2 is associated with hyperprogression?

Mdm2 inhibitor inhibits mTOR   

In 2010, our studies demonstrated that Mdm2 inhibitors inhibit the mTOR pathway in cancer cells [11, 12].

While blocking cancer cell proliferation, The MDM2 inhibitor, nutlin-3a, prevents the senescent phenotype with a pro-inflammatory SASP, by inhibiting mTOR [13].

The effect of Mdm2 inhibitors on mTOR, SASP, and pro-inflammation mirrors the effect of rapamycin [11], [14] [13], [15], [16].

Hyperfuctional mTOR potentially causes of hyperprogression and side effects

  Hyperfunctional mTOR could potentially contribute to hyperprogression and side effects associated with immunotherapy. By drawing connections from seemingly unrelated fields, it becomes apparent that overactivated mTOR might partially be responsible for these negative outcomes. Moreover, mTOR-driven inflammation could diminish the therapeutic effect of immunotherapy. And mTOR inhibitors, rapamycin and everolimus, may potentiate therapeutic response. Treatment with rapamycin may especially benefit patients with cancer overexpressing Mdm2. 

Given that Mdm2 inhibitors are not currently approved for human use, we might alternatively consider employing rapamycin and everolimus. These agents, both mTOR inhibitors, could potentially offer similar therapeutic benefits in the interim. And also importantly they decrease side effects of immunotherapy, while increasing the efficacy. 

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