Injecting hope- Improving outcomes in relapsed high

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Injecting hope: Improving outcomes in relapsed high-risk neuroblastoma with a bivalent vaccine Linda D’Andrea, RN, PPCNP-BC, CPHON and Melanie Cohen, RN, BSN, CPHON Pediatric Ambulatory Care Center; New York, New York

Methods

Background

Results (continued)

The bivalent vaccine includes NB associated GD2-KLH/GD3-KLH conjugate vaccine mixed with 150 µg/m2 of adjuvant OPT821.

High–risk Neuroblastoma (HR-NB) has long been associated with high relapse rates and poor survival. The advent of immunotherapy using anti-disialoganglioside (GD2) monoclonal antibodies, which target the GD2 glycolipid antigen found on the surface of NB cells and treat microscopic residual disease (MRD). This has improved progression-free survival up to 50-60%; however with relapse, the chance of cure falls considerably to <20%. New treatment options are critical to improving outcomes in relapsed HR-NB.

7 injections are administered subcutaneously in the outpatient setting over 52 weeks. Oral β-glucan at 40mg/kg/day begins at week 6 and continues 2 weeks on, 2 weeks off for 13 cycles. The drug is administered by a trained research nurse and the clinic visit is overseen by a nurse practitioner.

Treatment Schedule

Phase II Study of Bivalent Vaccine Enrollment

84

5

Very high risk group

5th to 7th remission

82.7%

70.4%

• Confirmed safety of the GD2-KLH/GD3-KLH vaccine • Improved OS and PFS in children with ≥ 2nd relapse of HR-NB • Short and infrequent outpatient clinic visits, along with minimal side effects, allow for quality of life

References

Results

v Progression-free Survival (PFS) at 21 months was 54% ± 6% v Overall Survival (OS) 90% ± 5% Progression Free Survival v No toxicity ≥ grade 3 reported ³ 2 n d

Patients with multiple relapses; they received vaccine after obtaining remission

R e m

is s io n

P a t ie n t s

s u r v iv a l

v Common side effects include: v Fever v Rash v Pain with SQ injection

P e r c e n t

N

4

During intervals during vaccine/followup

Conclusion

1 0 0

4th remission

29.4%

(Cheung et al., 2018)

Progression-free survival and overall survival estimated by Kaplan Meier analyses

The study opened as a phase 2 in 2013 and 84 patients with relapsed HR-NB in ≥2nd remission were treated. All patients had prior exposure to anti GD2 immunotherapy with either m3F8, Naxitamab, or Dinutuximab. The breakdown was as follows:

18

13.3%

• Expected side effects of pain and/or neuropathy not seen with development of anti-GD2 antibody titers

* HR-NB as defined by INRG staging system with disease resistant to standard chemotherapy and either: • MYCN-amplified (any age at dx): stage 4, 4s, or stage 3 (unresectable) • MYCN-non-amplified: stage 4 ≥ 18 months at diagnosis

3rd remission

Pre-vaccine

• No impact on patient outcome based on pre-vaccine anti-GD2 serum titer

In 2009, a phase I trial used bivalent vaccine in combination with β-glucan to treat 15 HR-NB* patients in second or later remission. No dose limiting toxicity was found and β-glucan was well tolerated. Relapse free survival (RFS) at 24 month was 80% +/- 10% (Kushner et al., 2014).

57

anti-GD3 titer

• Developing anti-GD3 response had no prognostic significance for survival

History of Bivalent Vaccine

2nd remission

anti-GD2 titer

• Anti-GD2 antibody titer >134ng/ml/month prognostic for improved PFS and OS

The bivalent vaccine* contains GD2 and GD3 glycolipids (both abundant on NB) and OPT-821, an immunological adjuvant that can stimulate the recipient’s immune response. It is given in conjunction with β-glucan, an immunostimulant. The aim is to induce the patient to generate antibodies against GD2 and GD3 and thereby eradicate MRD and improve survival (Kushner et al., 2014). *Licensed by Memorial Sloan Kettering Cancer Center and Mabvax to Ymabs

≥ second remission

% patients with positive

Image courtesy of Dr. Nai-Kong Cheung

What is Bivalent Vaccine?

2013 to 2017

Serum anti-GD2 and anti-GD3 IgG1 antibodies were measured

Kushner, B. H., Cheung, I. Y., Modak, S., Kramer, K., Ragupathi, G., & Cheung, N. K. (2014). Phase I trial of a bivalent gangliosides vaccine in combination with β-Glucan for high risk neuroblastoma in second or later remission. Clinical Cancer Research, 20, 1375-1382. Kushner, B., Modak, S. (2012). Phase I/II Study of Combination Therapy of Antibody Hu3F8 with Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in Patients With Relapsed/Refractory High-Risk Neuroblastoma. Identification No. NCT01757626. Retrieved from https://clinicaltrials.gov/ct2/show/NCT01757626?term=kushner&rank=3

5 0

O S P F S 0 0

2

T im

e

f r o m

s t a r t in g

4

v a c c in e

6

( y e a r s )

(Cheung et al., 2018)

Cheung, I., Kushner, B. H., Modak, S., Ragupathi, G., Roberts, S., Basu, E. et al. (2018). Phase II Trial of GD2-KLH/GD3-KLH Vaccine for Stage 4 Neuroblastoma In ≥2nd Remission: Induced Anti-GD2 Titer Strongly Correlates with Survival. Advanced in Neuroblastoma Research Association Meeting. Retrieved from https://www.anrmeeting.org/anr2018-abstracts/meetings-2018_abstracts.php