Ophthalmic Immune Related Adverse Events

January 10, 2020

Information

Yale Cancer Center Grand Rounds | January 7, 2020

Renelle Lim, MD

ID4743

To CiteDCA Citation Guide

00:04Yeah.
00:10Alright hello, we can get started. We have a forum and everybody's already still quiet so I come to the first grand rounds of the year. It's my pleasure to introduce the speakers today, so right now. Lim will be our first speaker. She's assistant professor of ophthalmology and visual science and she's a director of the smilow cancer hospitals ocular oncology program.
00:34She received her MD from the State University of New York Downstate Medical School and also trained under Carol Shields and will die. Husband Philadelphia, Philadelphia and she completed 2 fellowships when an ocular plastic surgery and in ocular oncology and she is the director of the archaeology program and sees patients was common and rare malignancies of the eyes and will speak to us today about ophthalmic immune related adverse events, so by contacting him.
01:08Thank you so much for the kind introduction, my name is Ronald Lemon. Today I'll talk to you about the ophthalmic immune related adverse events and share our experience, I have no financial disclosures, although a few of my coauthors are consultants.
01:27Today we'll discuss the mechanism. The mechanism of action of checkpoint inhibitors and detail a few cases. We can all agree that the relationship between the immune system and cancer is complex with the realization that cancer finds ways to escape detection by the immune system trends in treatment have focused on methods to interrupt cancer tolerance and reactivate the immune system against tumor antigens.
01:58Target recognition by T cells is a 2 step process. The 1st is an interaction between the T cell receptor and that MHC complex or major histocompatibility complex displayed by tumor cells or antigen presenting cells.
02:14The 2nd event is a Co regulatory signal that determines whether the T cell becomes activated or down regulated and the 2nd event will be illustrated here.
02:26You can think of CTLA for a receptor on the surface of activated T cells as one of the brakes of the immune system because it functions to down regulate the T cells to help prevent autoimmunity an inflammation.
02:42When the interaction of B7 and CTL E4 takes place it's like stepping on the brakes inhibiting the TSLT cells also expressed another receptor called CD 28, which is Constitu Tively expressed and serves an opposing function to CTL A4.
03:01Triggering T cell activation when CD 28 binds to be 7. It's like stepping on the gas pedal and the T cell remains active to go kill cancer.
03:14CTL A4 competes with CD28 for B7 binding, but CTL A4 has a much higher affinity to kill cancer cells. The cytotoxic T cell should remain active so how do we keep the T cell active?
03:32By preventing the binding of Ctla 4. NB 7 altogether in 2011. the FDA approved it belimo map a monoclonal antibody for treatment of advanced metastatic cutaneous Melanoma. It's been 9 years since approval of it be limam anti. PD one and P. DL1 way later approved by the FDA based on successful. Large, randomized, controlled clinical trials now immunotherapy is considered one of the pillars of cancer therapy.
04:03Prior to the introduction of immunotherapy the 10 year survival rate for metastatic Melanoma was less than 10%.
04:11Survival rates for Advanced Stage 3 or 4 unresectable meta static cutaneous Melanoma are even better when combination therapy is employed. The five year data was recently published demonstrating that the overall survival of advanced metastatic Melanoma was 52% in the combination group of Nuvola. Mab and if you limo. Mab there are currently 7 FDA approved immune checkpoint inhibitors.
04:40And the indication for use of immune checkpoint inhibitors are continually growing to not only involve unresectable advanced metastatic cutaneous Melanoma, but squamous cell carcinoma of the head and neck. Merkel cell carcinoma of paddle cellular carcinoma renal cell carcinoma cervical cancer and the list continues.
05:04We recently published our experience with immunotherapy and the atomic immune related adverse events because the use of immunotherapy continues to grow the adverse events will expand and it's important to be mindful that there are ophthalmic immune related adverse events.
05:26We reviewed the charts of almost 1500 patients and 15 of them or 1% developed in al thalmic immune related adverse event. Most patients were treated with combination therapy. It belima map and Nuvola Mab, the most common ophthalmic immune related adverse event was uveitis.
05:47Interesting Lee all patients who had ophthalmic immune related adverse events also had concomitant systemic immune related adverse events such as colitis dermatitis arthritis. Hepatitis Hypophysitis and the list goes on.
06:07Now let's discuss a few unique cases.
06:11This is a 75 year old man with a history of left foot Melanoma, who developed widespread metastasis. He was treated with two cycles of hippie anevo and complained of seeing distorted images anterior segment examination showed an irregular pupil.
06:30And you can see a little bit of scarring and this is what we call posterior synechiae where the iris is adherent to the anterior lens capsule. This patient was managed with Topical Corticosteroids Topical Prednisone.
06:47And after one month you see release of the posterior sneaky and he now has around pupil.
06:54So I mentioned that uveitis was the most common ophthalmic immune related adverse event and I'd like to take a minute to just talk about what uveitis is it simply inflammation of the UV A and the uvea consists of the iris. The ciliary body and the choroid.
07:12Uveitis can manifest in many different ways patients can present with debris on the back of the Corneal. The Corneal endothelium and we call this keratic precipitates.
07:26Our patients can have cells in the anterior chamber. Usually, it should be white and quiet. Usually, it should be quiet. But when cells are present. We know there's some underlying inflammation.
07:38Or have posterior synechiae and that's anterior uveitis, but UV I just cannot affect the back of the eye. More and we call that posterior the ritis or core roditis and you can see inflammation affecting the choroid and sometimes the retinal vascular cherr.
07:57Here's another case a 57 year old woman with a history of choroidal Melanoma and you see a pigmented.
08:06At lesion affecting the choroid, she was treated with black breakey therapy and you see very nice regression of the pigmented lesion, however. Later, she developed liver metastasis. She was treated with hippie. Lumaban nuvola mab and receive just one cycle. She then developed a rash in 2 weeks later, she presented with left upper eyelid ptosis and diplopia a work up was performed and she had elevated CK levels.
08:36Myositis elevated proponents myocarditis an she had acetylcholine. Receptor antibodies and she was diagnosed with myasthenia gravis myositis and myocarditis. She was hospitalised and treated with intravenous corticosteroids immunoglobulins empire, it'll stick mean and she had complete resolution of her ophthalmic symptoms at 6 months. However, she did have progression of disease in later received radio embolization for worsening liver metastasis.
09:10This is a case report an I thought this was interesting because it's very similar to our patient an the authors described in 80 year old man with a history of cutaneous Melanoma metastatic to lymph nodes who developed fatigue shortness of breath, Weekness After 2 weeks 2 weeks after starting nuvola. Mab the authors obtained baseline acetylcholine. Receptor antibody level in this patient had low levels of acetylcholine receptor antibodies.
09:42However, after treatment with nuvola mab, we can see a spike in the acetylcholine receptor antibodies in it.
09:51And after immunoglobulin you see the acetylcholine receptor antibody level decrease in the same was true for the CK levels.
10:02The patient had a skeletal muscle biopsy T cell receptor analysis using next generation sequencing identified infiltration of Clonally expanded T cell populations in skeletal muscle after treatment with nuvola mab and these high numbers of T cells found in the skeletal muscle biopsy suggest a strong T cell immune response against muscular skeletal, muscular cells. Here's another case a 43 year old woman with a history of metastatic cutaneous Melanoma.
10:35Received 3 cycles of it being evil.
10:38She complained of blurry vision.
10:41Fundoscopic examination showed choroiditis and you can see the areas of inflammation affecting the core ride. She was treated with systemic corticosteroids with improvement in her visual acuity and she achieved 2020 vision in both eyes. An she had a complete response to treatment and is now followed every six months.
11:04Here's another case a 54 year old women with a history of Angel Melanoma with brain metastasis who is treated with combination therapy who also complained blurry vision, Visual Acuity was 2070. In both eyes in the photos at the Top. This is called optical coherence tomography and this is our version of a see T scan of the eye and it essentially scans. The retinal layers and you can see fluid deep to the retina.
11:34This patient was treated with systemic corticosteroids with improvement in her visual acuity to 2025 in both eyes. However, she had progression of her metastatic disease and is now deceased.
11:48This is another interesting case of a 61 year old woman with a history of metastatic cutaneous Melanoma who complained of blurry vision, especially of the left eye. Funduscopic examination showed bilateral disk adima you can see swelling of the optic nerves visual field testing showed severe constriction.
12:08Everything that you see outlined in black is an area of her visual field that she could not see so this patient was treated with systemic corticosteroids. However, there was no improvement in her best corrected visual. Acuity immunotherapy was stopped because the patient also had low ritis and floral Fusion, she had progression of disease, Ann is now deceased.
12:33This is another case of a 54 year old man with a history of metastatic cutaneous Melanoma who received one cycle of combination therapy and complained of progressive visual loss.
12:47Here you can see pockets of subretinal fluid and you see yellow material. It's forming a little bit of a meniscus. We call this patelliform material. So you see 1 central large pocket of fluid an multiple satellite pockets of fluid.
13:05This patient was diagnosed with acute oxidative polymorphous the Teleform Maculopathy, an the subretinal fluid was confirmed an optical coherence tomography.
13:21This is a report of a patient very similar to the one I just described but the patient developed acute exit dative polymorphism. Patelliform maculopathy after me. Rafa nib and pembrolizumab with similar clinical features, however, not as dramatic as our patient.
13:41A 79 year old women with metastatic cutaneous Melanoma complained of Photopsia. We're seeing flashes of light just after one cycle of a belimo mab and Nuvola Mab.
13:54Her funduscopic examination was completely normal there was no deviation from baseline. No evidence of chorditis know subretinal fluid. No evidence of uveitis so she went on to receive another cycle of combination therapy. Then she developed transaminitis.
14:12Hypophysitis and Dermatitis as well as worsening of her ophthalmic symptoms, worsening photopsia and she had difficulty seeing at night nyctalopia.
14:24Because of her trans amanita sin hypopituitarism. She was treated with intravenous solu medrol with without resolution of her ophthalmic symptoms. At this point Melanoma associated retinopathy was high on the differential.
14:41So, an electroretinogram was performed and if you look to the left, you can see what a normal. I will look like the B wave has that very high amplitude indicated by the arrow. But in our patients right and left eye. She had a severely attenuated be wave.
15:00Which shows bipolar loss of bipolar cell function?
15:05Anti retinal antibodies were also obtained an were positive in our patient and she was diagnosed with Melanoma associated retinopathy.
15:14So how do we treat these conditions if mild and if uveitis is just anterior we can treat these patients with topical Prednisolone?
15:26In more advanced cases, we can administer steroids via injection. Perry ocular injections or intravitreal injections. An tored the right. You can see a Depot. The white material is kenna log and there's a Depot in his superior, temporal fornix here. Sometimes patients are managed with Prednisone others. Other times patients have to undergo treatment with corticosteroids or immunoglobulins an rarely do we use plasma pheresis?
16:02In summary immune checkpoint inhibitors are powerful agents, which allow cytotoxic T cells to remain active in attack cancer cells.
16:13The atomic immune related adverse events are real.
16:17The incidents is about 1% an can occur within weeks to months of therapy and can affect various parts of the eye and orbit.
16:31Patient can patients can have dry eye conjunctivitis keratitis uveitis serious retinal detachment optic neuritis.
16:41Autoimmune Retinopathy Choroiditis Myasthenia Gravis.
16:47An myositis so when these patients have dry eye.
16:52These can be managed with Topical Lubrication.
16:58Patients can present with conjunctivitis where you see redness of the conjunctiva and these are mild symptoms and can be managed with eyedrops. However, keratitis can be more visually debilitating in cause blurry vision. We actually had a patient who had a corneal perforation.
17:17Where the cornea actually opened and the intra ocular contents? Can then be extruded if the keratitis is severe?
17:25UV ritis we talked about posterior sneaky a we talked about anterior chamber cell.
17:33Serious retinal detachment swear there's fluid underneath the retina.
17:40We talked about optic neuritis or optic disc edema and loss severe loss of visual field function.
17:50Autoimmune Retinopathy again, these patients can have a normal I exam normal fundoscopic findings.
17:58ERG or electroretinogram will show an attenuated be wave, which show which signifies loss of bipolar cells.
18:07And we discussed Cora Dietis, where I remember the core right is part of the UV and so this is a type of posterior uveitis. Our patients who had a uveal Melanoma developed my senior gravis after just one cycle of combination therapy and she presented with left upper eyelid ptosis and double vision.
18:31And here's an example of what myositis looks like of the extraocular muscles. You see the medial rectus enlarged in axial in Corona views.
18:42Impatience can present with cranial nerve palsies as well.
18:47Thank you.
18:57Any questions with temple questions.
19:02So I have.
19:05Notice.
19:09How often do you?
19:12The perspective in comparison to the junior right? That's a great great question the question was.
19:23How does the use of immune checkpoint inhibitors differ for uveal Melanoma when compared to cutaneous Melanoma?
19:33Unfortunately, when uveal Melanoma metastasizes there is no great treatment. So we employ the use of immune checkpoint inhibitors. However, about 10 to 15% of patients will respond does not have a great overall survival that cutaneous Melanoma has.
19:52An in that patient, she actually still had progression of disease, she only received one cycle of combination therapy. But she had to undergo radio embolization.
20:06To be more questions.
20:08I've a question so do you see a correlation between the types of symptoms. You see in the eyes and their systemic side effects on in our study. We did not see that now. Some people hypothesize that if patients develop immune related adverse events that these patients are more likely to respond to immunotherapy and more likely to have an improvement in overall survival. But when looking at the ophthalmic immune related adverse event there was no correlation.
20:39As just wondering about the etiology of the optic neuritis. You don't biopsy anything there. So you're just seeing the papilledema or the disc edema right so do you know what's going on? Is it art easels infiltrating the optic nerve is an antibody mediated or nobody knows or not you know it's immune related I think that's what I meant.
20:58Well, in that we have to put the whole picture together in this setting of using immune checkpoint inhibitors in again. These patients when they present with a thaumic immune related adverse events. They also have other types of inflammation in the rest of the body so.
21:13Yeah, we can assume that this is all related to immunotherapy, but no one is.
21:22So, in that case, she did receive corticosteroids. However, there was no improvement in the vision vision. And that was a severe case. She had a severe constriction in her visual fields. So it's very difficult to have that normalized.
21:43Do you have any additional questions in the middle? I'm not sure I need to make it there?
21:48Hello.
21:57And.
22:04So the question was how long does it take between the diagnosis of Melanoma an the actual symptoms So what we looked at was not necessarily the time of diagnosis of Melanoma, but more when immune checkpoint inhibitors were started and from the time when the immune checkpoint inhibitors are started to the time of ophthalmic immune related adverse events.
22:35It varies from weeks to several months.
22:42More questions.
22:45No OK OK. Thank you very much.
22:49Right.