What is the current state of anti idiotype vaccines?


(Sam Saffron) #1

There are 2 anti idiotype vaccines in the pipeline.

mAb 1A7 by Dr. Alice Yu and team.

mAb1A7 is an anti-idiotype antibody directed against a murine anti-GD2, 14G2a, and in effect, mimics the GD2 antigen. Yu et al conducted a clinical trial of mAb 1A7 as a surrogate GD2 vaccine in 31 patients with high risk neuroblastoma who achieved first or subsequent responses (74). There were no systemic toxicities seen with subcutaneous injections given periodically over two years, but only local reactions, transient fever in four patients and serum sickness in one. All patients generated anti-mAb1A7 and their immune sera displayed CDC and ADCC activities. Sixteen of 21 patients who enrolled during first remission had no evidence of disease progression at a median of 6 years, while only 1 of 10 patients in second remission remains progression free. These findings indicated that mAb1A7 vaccine has little toxicity, is effective in inducing biologically active anti-GD2, and may be useful in controlling MRD (75) (unpublished data from Yu et al).

There is also the slightly newer anti idiotype vaccine by Dr. Holger Lode and team

Importantly, patients vaccinated with 1A7 showed little side effects which underlines the suitability of such a vaccine for clinical application. To provide unrestricted access for clinical development in Europe, we recently generated and characterized a murine anti-Id Ab ganglidiomabwhich paratopes mimic GD2.

In summary, we describe the generation and characterization of a new chimeric anti-Id Abganglidiximab used as a protein vaccine to induce humoral immunity against NB in mice. Our results are an important baseline for further development of new anti-Id Ab-based vaccination approaches against GD2-expressing malignancies

https://www.researchgate.net/publication/297890998_Generation_and_Characterization_of_a_HumanMouse_Chimeric_GD2-Mimicking_Anti-Idiotype_Antibody_Ganglidiximab_for_Active_Immunotherapy_against_Neuroblastoma

Having an accessible vaccine is at the top of the list for parents. Current immunotherapy approaches only have an effect while children are treated, they do not have any lasting protective effect. A vaccine could protect children for many years and avoid countless relapses.

I was wondering if anyone knows

  • Are there any open trials (phase 1/2) for an anti idiotype vaccine?

  • Is there anything parents can do to help drive innovation around either vaccines?

  • What happened with 1A7? Are there any phase 2 trials, now that toxicity levels are clear?


Unituxin (dinutuximab) worldwide shortage
(Sam Saffron) #2

I emailed Alice Yu regarding mAb 1A7, the current state is that it would cost 1.5-2.5 million dollars to start a new trial. She is negotiating with some biotech companies that may help out, but it is basically blocked on funding.


(Alexey) #3

I sent email to Dr. Lode about readiness of their vaccine, but no reply yet. Will try to contact him via our oncologist.


#4

I asked this very question of dr lode at the CNCF - he said he is unable to say when it will be available at best he said some time away.


(Alexey) #5

Thanks, seems only 2 options currently available for the maintenance treatment: the vaccine from MKSCC and DFMO…
Have you heard any discussions about both of them on that conference?


#6

There was lots of discussion - too much to go into here appropriately but the talks will be uploaded soon for everyone to watch. SIOPEN are launching a trial soon called veritas for refractory disease


(Sam Saffron) #7

VERITAS is very similar to an upcoming COG study, the idea is to integrate MIBG treatment into frontline is some cases. I think COG will also only do it for refractory.

I am very curious to hear if Dr. Kushner has any new data about the efficacy of the vaccine now that it has been in stage 2 for almost 2 years and is given to all NB high risk patients in MSKCC.

The thing I find particularly frustrating about mAb 1A7, is that it has been around for many years and showed definite promise as a maintenance treatment after frontline. 1.5-2.5 million dollars is what some people raise for treating a single child, this has potential benefit for many many more. Yet Dr. Yu is blocked purely on money here.

I am not sure if this is something @KyleMatthews and @Patrick_Lacey could help drive with Beat NB?


(Kyle Matthews) #8

Our funds aren’t at a place currently where we’d be able to consider this.

I wonder what the bulk of that cost is? That seems high (maybe it’s the actual creation of the vaccine?).


(Sam Saffron) #9

I am not sure, perhaps you could call Dr. Yu and discuss?

I think there is more than just money can help, if there is more awareness perhaps other charities etc can help?

Band of Parents managed to raise 2M$ to humanize 3F8 and that particular effort only really helps people being treated in MSKCC. Perhaps they can offer some advice or help in this department?


(Kyle Matthews) #10

Good idea. I’d love to see more of the work at Sloan being offered in other institutions, too.


(Donna Ludwinski) #11

We started conversations with both Dr Lode and Dr Yu 4+ years ago, and yes money and finding companies to commercialize the product are the only blocks. Both anti idiotype antibodies have been created and the clinical grade have been tested in children. Lode needs 500,000 euros to produce a single batch with a contract company (manufacture only, not drug development costs that include regulatory costs). But he still needs a company to commercialize the drug. Similarly Yu is trying to engage a biotech to actually take to market which includes an enormous amount of regulatory costs above and beyond just producing the anti idiotype antibody. They need investors. Her plan is to test in Asia, which is needed especially since they have no antibody, but very unlikely that data could be used for FDA or EMA approval. Ideally, eventually this should replace antiGD2 antibodies since admin and side effects are big issues. See ASCO 2010 Education Book, Alice Yu wrote about this.


(Kristen Wilson Mitchell) #12

Were new to looking for treatment beyond the siopen protocol my daghter is on and an getting mixed reactions from our drs when i try and bring up the subject I feel like they just dismiss us with regards to further treatment I spoke with my daughters prof about the DMFO trials in america and was told they are unproven results and they feel its not something worth looking at grr. is there anywhere i can get some in depth information about this vaccines i really want to make sure i have all the information so i can go to our DR again and make sure we do everything we can to make sure our baby girl stays NED.


(Sam Saffron) #13

@Tomislavcroatia I was wondering if you can query Dr. Lode about his vaccine trial status, my understanding is that he and some parents are trying to mount a clinical trial within the next 12 months but unsure of the exact details.


(Alexey) #14

Does anybody know of what happened with this trail?


(Mark Shirran) #15

I just confirmed with one of the Bristol oncologists that they had the funding but the company decided not to make the vaccine available in the end. So frustrating! :frowning:


(Tomica Tomek) #16

Dear Sam
. We are going to Griefswald on 09.01.2017.
I will ask prof Lode about vaccine trial. And i will let you know


#18

I and one other parent were exploring the option of getting funding together to find d a gmp batch of lodes anti idiotype. We discussed at siop 2016 with him it has not gone any further. Is that what you are referring to? We did look at attracting other funds


(Tomica Tomek) #19

I spoke with Prof Lode one month ago about anti idiotype. He told me that he cannot tell me when this will start but it will in near future.


(Alexey) #20

Phase II Trial of GD2-KLH/GD3-KLH Vaccine for Stage 4 Neuroblastoma In
≥2nd Remission: Induced Anti-GD2 Titer Strongly Correlates with Survival
Irene Cheung, Brian Kushner, Shakeel Modak, Govind Ragupathi, Stephen Roberts, Ellen Basu, Anupa
Kudva, Nai-Kong Cheung (Memorial Sloan Kettering Cancer Center, New York, United States)

Background: Anti-GD2 antibodies mouse 3F8 and hu3F8 have proven survival benefit in patients with high
risk stage 4 neuroblastoma (HR-NB). Both antibodies induced de novo anti-GD2 antibody response. A Phase
I vaccine trial utilizing GD2-keyhole limpet hemocyanin (KLH)/GD3-KLH in 15 patients found no dose-limiting
toxicities (Kushner et al., CCR 2014).

Methods: In this Phase II trial, 7 doses of 60ug of GD2-KLH/GD3-KLH conjugate vaccine mixed with 150ug of
adjuvant OPT821 were administered subcutaneously in outpatient setting over one year in 84 patients with
HR-NB in ≥2nd remission; oral yeast beta-glucan at 40mg/kg/day x 2 weeks q month x 10 months was
included to enhance antibody mediated cytotoxicity. Progression-free survival (PFS) and overall survival (OS)
were estimated by Kaplan Meier analyses.

Results: All 84 patients had prior relapse, 57 treated in 2nd remission, 18 in 3rd remission, and the rest in
4th to 7th remission. All had prior exposure to either mouse 3F8 (63%), and/or hu3F8 (57%), and/or
dinutuximab (46%). Median follow-up was 16 months; PFS was 51%±7% and OS were 90%±5% at 2 years
with no ≥grade 3 toxicities. Serum anti-GD2 and anti-GD3 IgG1 antibodies were measured using ELISA at
serial time points, integrated, and expressed as area-under-the-curve per month. Anti-GD2 titer was
positive pre-vaccine in 14% of patients (median=39ng/ml), and positive post-vaccine in 78% (median=134
ng/mL/month). Developing anti-GD2 antibody titer did not result in any patient having pain or neuropathy.
There was no correlation between pre-vaccine and post-vaccine titer. Anti-GD2 antibody titer>134ng/ml/month was prognostic for improved PFS and OS (p=0.033 and 0.025, respectively). In contrast,
developing anti-GD3 response had no prognostic significance for survival. There was no impact on patient
outcome based on age at diagnosis, time from diagnosis, MYCN amplification, number of prior relapses, prevaccine anti-GD2 antibody therapy, as well as pre-vaccine anti-GD2 serum titer.

Conclusion: These results confirmed the safety of GD2-KLH/GD3-KLH vaccine and the potential influence of
anti-GD2 but not anti-GD3 seroconversion on PFS and OS. If the 90% OS is confirmed in a phase III
randomized trial, GD2 vaccine could provide a viable option to improve the outlook for patients with
relapsed HR-NB.

From here (page 114): http://anr2018.org/wp-content/uploads/2018/05/ANR-Abstract-Book-5.9.18.pdf