Symptoms and General Pathology

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Syndrome

All Drugs and Chemicals

Antibodies

Immunomodulating Agents

Immunoglobulins

Immunoglobulins, Intravenous

gamma-Globulins

Rho(D) Immune Globulin

Immunologic Factors

Immunoglobulin

Dimitri Psimaras, MD

Paraneoplastic Neurological Syndromes (PNS) are rare remote effects of cancer, not directly attributed to mass lesions, metastases, infections, ischemia, coagulopathy, metabolic disruptions or tumour treatment. Currently, PNS treatment is mostly limited to tumour treatment. Because of an initial inflammatory stage early in the evolution of the PNS several immunotherapy modalities have been tried. Intravenous human immunoglobulins could be expected to provide a stabilization or even improvement of PNS, if administered early enough to prevent permanent neuronal damage.

Paraneoplastic neurological syndromes (PNS) are remote effects of malignant neoplasia on neural tissue, not directly caused by mass lesions, metastases, infections, ischemia, coagulopathy, metabolic disruptions or treatment. The symptoms and signs of PNS are diverse, usually acute or subacute. Onconeural antibodies are detected in their serum, and sometimes in their Cerebrospinal Fluid (CSF); onconeural antibodies are highly specific for identifying patients with neurologic symptoms as having a paraneoplastic syndrome. The most frequent ones are anti-Hu, anti-Yo and anti-CV2/CRMP5. Although a known cancer patient may present with a PNS, neurologic symptoms precede other manifestations of a tumor in about 65% of patients.

Currently, autoimmunity is postulated to underlie the pathophysiology of PNS. Tumor cells can sometimes express antigens normally found only in the nervous system, an immunologically privileged site. Onconeural antigens on tumors can be identified as foreign by the immune system and an immune attack can be elicited against them. In the subset of PNS patients, the immune system could also recognize and attack onconeural antigens in normal nervous tissue. This autoimmune hypothesis for the pathogenesis of PNS is supported by a series of arguments: Onconeural antibodies are found in serum and CSF; Cerebrospinal fluid studies show inflammation in 93% of patients; In the acute phase of paraneoplastic cerebellar degeneration hypermetabolism in 18F-Fluoro-2-Desoxy-Glucose Positron Emission Tomography (FDG-PET) scan and increased perfusion on Single Photon Emission Computed Tomography (SPECT) have been described and attributed to inflammatory changes; Pathological examination of the nervous system from patients with anti-Hu associated paraneoplastic encephalomyelitis demonstrates loss of neurons in affected areas with extensive T-cells infiltration and immunohistochemical studies on damaged neural tissue after autopsy reveal inflammatory infiltrations.

Effective treatment of PNS requires an early clinical suspicion followed by rapid diagnosis, through detection of onconeural antibodies, and identification of the underlying tumor. Unfortunately appropriate treatment of the cancer is most often unsuccessful to improve neurological symptoms and these patients are generally left bedridden until death. It's seems important to associate an immune treatment but has never been adequately tested. Experience with immunotherapy modalities, such as corticosteroids, plasma exchange, immunosuppressants or human intravenous immunoglobulin (IVIg), relies on case reports, retrospective studies, and a couple of prospective studies in patients generally treated at a late stage. To date, it has not been possible to set up a prospective therapeutic trial evaluating the role of early immune treatment, administered less than 6 months after the onset of symptoms, in these patients. Considerable evidence for an initial inflammatory stage (early in the evolution of the PNS), and isolated case reports of early immunological intervention suggest that this approach may be valid to treat these disorders. Because IVIg are often use in neuro-immunological disorders (ex. first-line therapy in Guillain-Barre syndrome, chronic inflammatory demyelinating polyradiculoneuropathy, multifocal motor neuropathy and dermatomyositis) with little and well known side effects and no interaction with cancer treatment we decide to use IVIg for our trial.

The Aim of the study is to improve neurological impairment and function in patients with early diagnosis of various PNS associated with well-characterized onconeural antibodies anti-Hu, anti-Yo, anti-CV2/CRMP5. The primary endpoint of the study is the percentage of patients with neurological improvement after 3 months of immunotherapy with IVIg. "Success" is defined by ≥ 1 point lower score in the modified Rankin Scale (mRS) after treatment compared to baseline. This is a prospective, open-label trial explores the efficacy of drugs approved for treatment of immune-mediated neurological disorders given early in the evolution of PNS associated with well-characterized onconeural antibodies. A total number of 17 patients will be treated. This is a multicenter study carried under the auspices of the French National Reference Center on PNS.

Immunotherapy and Paraneoplastic Neurological Syndromes

Early Onset Immunotherapy by Intravenous Immunoglobulin in Well-characterized Onconeural-antibody-positive Paraneoplastic Neurological Syndromes

"Success" is defined by ≥ 1 point lower score in the modified Rankin Scale (mRS) after treatment compared to baseline. "Failure" is defined by failure to meet the success definition.

Progression-free survival at 6 months defined as the percentage of patients that remain neurologically stable after 6 months of treatment of defined by the mRS and the PNS Neurological Scale.

Assistance Publique - Hôpitaux de Paris

Nervous System Diseases

Substance Related Disorders

Neoplasms

Rare Diseases

Neurotoxicity Syndromes

Paraneoplastic Syndromes

Poisoning

Chemically-Induced Disorders

Antineoplastic Agents

Immune Checkpoint Inhibitors

Patients treated with ICIs who developed neurologic syndromes consistent with NirAEs, of grade ≥ 3 according to the Common Terminology Criteria for Adverse Events (CTCAE)

This is a non-interventional study. We will collect clinical data exclusively, and will do so by reviewing all available patients clinical records.

Immune-checkpoint inhibitors (ICIs) have radically changed the therapy of cancer in recent years. ICIs promote antitumor immune response inhibiting one of the following immune checkpoints: cytotoxic T-lymphocyte antigen-4 (CTLA-4; ipilimumab), programmed death-1 (PD-1: pembrolizumab, nivolumab, and cemiplimab), and programmed death ligand-1 (PD-L1: atezolizumab, durvalumab, and avelumab). Despite the desired effect as cancer treatment, ICIs can break immune tolerance to self-antigens and induce specific toxicities known as immune-related adverse events (irAEs), that may affect both peripheral and central nervous system (Neurological immune mediated adverse events, NirAEs). The pathogenic mechanisms underlying NirAEs are probably heterogeneous, as reflected by the variety of clinical phenotypes and severity.

NirAEs are rare, but there is some concern that the incidence may increase in the next future, in particular because ICIs are being used more and more for cancers commonly associated with paraneoplastic neurological syndromes (e.g. small-cell lung cancer). Moreover, NirAEs are usually severe, and often fatal. Indeed, irAEs-related complications are the most common cause of death among these patients. On the other hand, these patients usually have a good tumor response to immunotherapy. There is some evidence that irAEs may predict ICIs efficacy and consequently NirAE surivors are likely to have longer life expectancy than non-NirAE patients.

Therefore, it is of utmost importance to better characterize the long-term outcomes of NirAE patients in terms of neurologic disability and mortality, and to identify predictors of severe NirAEs. So far, only few studies with sufficient follow-up have been published on the topic, and they included only small number of patients.

The aims of our study is to characterize the main clinical and paraclinical features of NirAEs in a large cohort of NirAE patients, to assess long-term outcomes and to identify prognostic factors. This study will help define new guidelines regarding NirAE prediction and management.

CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.

Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.

Evaluation of residual neurological disability as assessed by the modified Rankin scale (mRS)

0 - No symptoms.

1. - No significant disability. Able to carry out all usual activities, despite some symptoms.
2. - Slight disability. Able to look after own affairs without assistance, but unable to carry out all previous activities.
3. - Moderate disability. Requires some help, but able to walk unassisted.
4. - Moderately severe disability. Unable to attend to own bodily needs without assistance, and unable to walk unassisted.
5. - Severe disability. Requires constant nursing care and attention, bedridden, incontinent.
6. - Dead.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Immunotherapy and Paraneoplastic Neurological Syndromes	NCT02343211	Paraneoplastic ...	Immunoglobulin	18 Years -	Assistance Publique - Hôpitaux de Paris
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
CICLOPS Immune Checkpoint Inhibitors Neurotoxicity: Long-term Outcomes, Predictors, and Survival.	NCT05942872	Paraneoplastic ...	This is a non-i...	18 Years -	Hospices Civils de Lyon
Immunotherapy and Paraneoplastic Neurological Syndromes	NCT02343211	Paraneoplastic ...	Immunoglobulin	18 Years -	Assistance Publique - Hôpitaux de Paris

Spots Global Cancer Trial Database for paraneoplastic neurological syndromes