Big antibody news

The “third generation” humanized anti-GD2 antibody with protein fusion of IL2 to the antibody has completed Phase I and II clinical trials for melanoma and neuroblastoma, and is now ready for use in Phase III clinical trials. The license for hu14.18-IL2 was just acquired by a small biotech in Vienna called Apeiron. The license was acquired from Merck.

Apeiron’s press release:

Apeiron Licenses Phase II/III Anticancer Ab-IL2 Fusion Protein from Merck KGaA

Long-term follow up of children with and without ch14.18/CHO in German trials NB90 and NB97

It has been a very long wait to finally see this graph. The Germans reported on this at ANR 2008 in Japan, and again at ANR 2010 in Stockholm.  See Graph A in Figure 2. “Follow-up analysis of the patient cohort indicated that immunotherapy with ch14.18 [no cytokines] may prevent late relapses.” Remember this group reported in 2004 “analysis failed to demonstrate an advantage of antibody treatment” –

http://jco.ascopubs.org/content/22/17/3549.long

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The statement about late relapses is a little puzzling to me. Graph A shows that “events” (which are usually relapses) occurred up until 10 years in both the ch14.18 and maintenance groups. Only the “no consolidation” group had later events.

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The authors concluded:”Today, the most effective way of antibody based maintenance therapy seems to be a combination immunotherapy with MAB ch14.18, cytokines, and retinoic acid. But these results need confirmation by at least another randomized trial. Further, metronomic low dose oral chemotherapy consolidation was found as effective as MAB ch14.18 consolidation in this retrospective analysis and, therefore, also warrants further evaluation. Prospective clinical trials must demonstrate if the concept of low dose metronomic chemotherapy is feasible and effective after ASCT and in combination with immunotherapy.”

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Since the early results did not show a benefit of ch14.18 without cytokines, and yet the COG trial showed 20% advantage in early results, it could be argued that there might be a big difference in survival between oral metronomic chemotherapy and ch14.18 with cytokines.

http://www.biomedcentral.com/content/pdf/1471-2407-11-21.pdf

Germans report on outcomes of relapsed NB patients who received three different regimens

Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials.

Simon, T., Berthold, F., Borkhardt, A., Kremens, B., De Carolis, B. and Hero, B. (2011), Treatment and outcomes of patients with relapsed, high-risk neuroblastoma: Results of German trials. Pediatric Blood & Cancer, 56: 578–583. doi: 10.1002/pbc.22693

This is an important publication and was presented at ANR 2010. Few groups have tackled relapsed NB in any systematic way. Wendy London’s abstract presented at ASCO 2010 and ANR 2010 on survival after relapse suggests that some relapsed NB children are salvageable, and the Germans and Swedes are advancing understanding in treating relapse. This same approach looking at more aggressive measures for relapsed leukemia kids is how relapse protocols were developed to treat relapsed leukemias.

Drs John Maris and Yael Mosse awarded patent for ALK mutation link to diagnosis, prognosis, and treatment of neuroblastoma

Summary of patent:

CHK1 suspected to be a promising target in NB — inhibitors are being tested in adults

‎”CHK1 mRNA expression was higher in MYC–Neuroblastoma-related (MYCN)–amplified (P < 0.0001) and high-risk (P = 0.03) tumors.”

RNAi screen of the protein kinome identifies checkpoint kinase 1 (CHK1) as a therapeutic target in n

www.pnas.org

Edited by Stephen J. Elledge, Harvard Medical School, Boston, MA, and approved December 17, 2010 (received for review August 23, 2010)

Protein May Be Key to New Treatment in a Childhood Cancer — PHILADELPHIA, Feb. 7, 2011 /PRNewswire-

Clinical and biological features predictive of survival after relapse of neuroblastoma: A study from the International Neuroblastoma Risk Group (INRG) Database.

Citation: J Clin Oncol 28:15s, 2010 (suppl; abstr 9518)

Wendy London is the Lead Statistician for neuroblastoma research for the Children’s Oncology Group (COG), and Data Center Statistics Committee Chair for the International Neuroblastoma Risk Group (INRG) project and has recently joined the team at Boston Children’s/Dana-Farber.

Dr London spoke on this topic at both ASCO 2010 (15 minute presentation on Monday for the Pediatric Oncology II session) and at ANR 2010 (25 minute presentation during the Monday Neuroblastoma Update Course)  and another 15 minute presentation on this same topic was given by by Victoria Castel on Thursday during the clinical plenary session. Three presentations–two at ANR!  This alone gives you an idea of the importance of this study–the largest ever done on this topic.

As I was preparing to report on this study, I saw that OncologySTAT.com (an excellent source of trustworthy oncology information by Elsevier, a world-leading publisher of medical information)  just released a report of their own. I highly encourage you to read their article.

Of 8800 INRG patients, 2266 experienced a “non-death first event.”

The INRG database includes all risk groups diagnosed from 1990 to 2002 in North America, Europe, Japan, and Australia.

Events are defined as relapse, progression, or second malignancy. Death as a first event was not included in this study.

Although prognostic factors are used to stratify treatment at diagnosis, no one has previously analyzed what factors are predictive of outcome post-relapse.  This study posed the question: is time-to-relapse a factor affecting outcome? Are there any other factors affecting outcome?

Of all the children who had events, median follow-up was 3.6 years (1 day to 13.7 years) and the characteristics of these children were:

• 73% ≥ 18 months old
• 72% were stage 4
• 33% were MYCN amplified

The median time to relapse for the 2266 children who had events was 13.2 months with a range of 1 day to 11.4 years. An anecdotal aside, I happen to know a fellow who relapsed 13.5 years after high-risk diagnosis, obviously not included in this data although he was diagnosed at Boston Children’s in 1991. He survived almost 5 years post-relapse.

The overall survival at 5 years after first event (all risk groups) is 20% ± 1%.

Those who had a first event in less than 1 year from diagnosis (n=1012) had approximately 25% overall survival and those who had first event after 1 year (n=1254) had about 10% overall survival.

When looking at those who relapsed before (n=2081) and after (n=184) 3 years, the gap closes at close to 20% survival.

The risk of death differs over time.

Time-to-first-event, age >18 mo, stage 4, MYCN amplified, diploidy, high MKI, undifferentiated grade, and 1p aberration were significantly predictive of death after relapse (p<0.0001), but not 11q aberration. Compared to children who had a first event more than 6 mo from diagnosis, those who relapsed 6-<18 mo from diagnosis had increased risk of death, while relapses ≥18 mo from diagnosis had decreased risk of death. Shorter time- to-first-event was not independently predictive of death after adjustment for undifferentiated grade, high MKI, MYCN amplification, or diploidy.

In a survival tree regression analysis that adjusted for time-to-relapse, disease stage was identified as the most highly significant variable for survival post relapse. Stage 4 patients (n=1578)  had a 5-year survival of 8% ± 1%, compared with 52% ± 3%  for those who were stage 1, 2, 3, or 4S (n=622).

Three groups were defined as salvageable for relapse treatment:

• stage 4, with nonamplified MYCN, and less than 18 months of age.
• stage 1, 2, 3, or 4S with MYCN amplification.
• stage 1, 2, 3, or 4S with nonamplified MYCN and undifferentiated grade histology.

Patients who had stage 4 disease and MYCN amplification had a 5-year survival of 4% ± 1% , compared with 12% ± 2% for stage 4 patients with nonamplified MYCN.

This information can help stratify children for relapse therapies.

NOTE: None of this data included how the children were treated for relapse. I am hoping this work will eventually lead to a rational plan for relapse therapy.

My take on this report? There WERE survivors in every group of relapse children….

Significance of abstracts submitted to ASCO

The meeting at ASCO (America Society of Clinical Oncology) provides a prime opportunity for oncologists and other researchers to present results of clinical trials and studies before publication in peer-reviewed journals.

This year ASCO had over 5000 abstracts submitted. Abstracts are reviewed for scientific and practice-changing merit and some are selected for either:

• Poster Discussion (a discussant comments for 15 minutes on up to 10 posters/abstracts)
• Oral Abstract Session (author speaks for 15 minutes on one study), with an expert in the field serving as discussant commenting 15 minutes on up to four Oral Abstracts.

The rest of the abstracts are shown in a the General Poster Session in a great hall where approximately 500 posters are displayed for a 4-hour period. The authors stand by their posters available for one-on-one discussion. This year a new session was added: Trials in Progress Poster Session.

At a higher impact level there are Education Sessions, Special Sessions, Award Lectures, Plenary Sessions, Scientific Sessions, Clinical Science Symposia, and so on for reviewing the state-of-the-art and continuing education.

Why explain this? It helps to understand the level of impact a particular study has by the assigned presentation format. The highest impact studies are the subjects of press releases by ASCO before, during, and after the meeting. Industry sponsors also produce their own press releases. For example, this year a high-impact study revealed the first-ever improvement in survival of melanoma in a phase III study. Last year the early results of the ch14.18 study was a pinnacle abstract of the 2009 meeting. These highlighted studies represent the top 0.2% of all abstracts submitted.

This year, therapy studies specifically focused on neuroblastoma did not rank quite that high, but there were results of some studies that included children with neuroblastoma. Five of the abstracts below were included in the poster discussion session (aurora a kinase inhibitor, lestaurtinib/CEP-701, pemetrexed, perifosine, and temsirolimus). There were 22 posters on the list for a one-hour presentation, so the discussants spoke somewhat generally about trial design and related issues concerning phase I and II trials, rather than specifics of the studies. Brief bits from the abstracts are included in the description, and my comments are in italics.

Results of therapies for neuroblastoma

Phase I trial MLN8237, an oral selective small molecule inhibitor of aurora a kinase. (Mosse et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9529)

37 patients were enrolled, 32 were evaluable for toxicity, recommended pediatric phase 2 dose and schedule of MLN8237 is 80 mg/m2/d administered once daily for 7 days. No response data reported.

Phase I trial of lestaurtinib for children with refractory neuroblastoma (NB): A New Approach to Neuroblastoma Therapy (NANT) Consortium study. (Minturn et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9532)

Lestaurtinib, a multi-kinase inhibitor with potent activity against Trk kinases, has demonstrated anti-tumor activity in preclinical models of human NB. 47 patients with recurrent or refractory high-risk neuroblastoma were enrolled, and 10 dose levels explored, two objective responses and 10 patients had prolonged stable disease at dose levels ≥5, (median: 12 cycles) before disease progression (pending review), recommended phase II dose of 120 mg/m²/dose BID, well tolerated in this heavily pre-treated patient group. The author said the manufacturer has no further interest in making this drug.

Phase I trial of oxaliplatin and doxorubicin in children and adolescents with recurrent solid tumors. (Mascarenhas et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9543)

Responding patients were treated for a maximum of 8 courses, 17 patients were enrolled, objective (≥partial) responses were noted in 3 neuroblastomas and 1 each of osteosarcoma, mixed germ cell tumor, neurofibrosarcoma, thymic neuroendocrine carcinoma and nasopharyngeal carcinoma, 4 patients completed all 8 courses of protocol therapy. Oxaliplatin 105 mg/m² on day 1 combined with doxorubicin 20 mg/m² days 1-3 was the MTD. Significant anti-tumor activity was noted.

Pilot study of the novel chemotherapy regimen of topotecan, ifosfamide, and carboplatin (TIC) in children with refractory/recurrent solid tumors. (Lee at al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9545)

The combination of ifosfamide, carboplatin, and etoposide (ICE) has previously been demonstrated to be an effective regimen in children with recurrent or refractory solid tumors (Cairo et al JPHO, 2001). Substituting topotecan (a Topoisomerase I inhibitor) for etoposide (a Topoisomerase II inhibitor) may be a more efficacious regimen due to the cytotoxic activity of topotecan in pediatric solid tumor xenografts, as well as its in vitro synergistic activity with platinum and alkylating agents. 14 patients (3-18 yrs) with relapsed/refractory disease (Wilms 2; osteosarcoma 2; germ cell tumor 2; high grade glioma 1; rhabdomyosarcoma 1; sarcoma 1; non-Hodgkin’s lymphoma 1; neuroblastoma 1; medulloblastoma 1; hepatoblastoma 1; neurocytoma 1). Disease response showed 4/14 with CR, 2/14 with PR, and 1/14 with SD for an overall response rate (ORR) of 43%. These preliminary results demonstrate that the combination of topotecan, ifosfamide, and carboplatin (TIC) is feasible, induces a >40% ORR in relapsed/refractory patients, and warrants further study in children with CNS and solid tumors.

Phase II trial of pemetrexed in children with refractory solid tumors: A Children’s Oncology Group study. (Warwick et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9535)

Pemetrexed is a multi-targeted antifol that inhibits key enzymes involved in nucleotide biosynthesis. Refractory or recurrent solid tumors to estimate the response rate and further define its toxicity profile. A two-stage design (10 + 10) was employed for each of the following disease strata: osteosarcoma, Ewing sarcoma/ peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET and non-brainstem high-grade glioma. Of 72 eligible subjects, 68 were evaluable for response. No complete or partial responses were observed. Stable disease, for a median (range) of 5 (4- 8+) cycles, was observed in 5 patients: ependymoma, Ewing sarcoma, medulloblastoma, neuroblastoma, osteosarcoma (n=1 each); one patient with Ewing sarcoma is still on study after 8 cycles. Although reasonably well tolerated, pemetrexed as administered in this study has no significant activity in a broad spectrum of refractory pediatric solid tumors.

Phase II study of temsirolimus in children with high-grade glioma, neuroblastoma, and rhabdomyosarcoma. (Geoerger et al) J Clin Oncol 28:7s, 2010 (suppl; abstr 9541)

Temsirolimus (TEMSR), an mTOR inhibitor, prolongs survival in adults with advanced renal cell carcinoma. Part 2 of the study explored the safety and efficacy in children with neuroblastoma, high grade glioma or rhabdoymyosarcoma. Primary efficacy endpoint was objective response (OR; complete response + partial response [PR]) within first 12 weeks. If fewer than 2 ORs occurred after 12 evaluable pts were enrolled in one of each tumor types, then enrollment in that tumor type would be stopped for lack of efficacy. 52 pts were enrolled (17 glioma, 19 neuroblastoma, 16 rhabdomyosarcoma), at 12 weeks, 2 pts had PR (1 neuroblastoma, 1 rhabdomyosarcoma). 11 pts achieved stable disease ≥12 weeks (5 neuroblastoma and 6 glioma). Two pts with neuroblastoma remain on treatment >2 years. Temsirolimus 75 mg/m2 was well tolerated, the OR rate failed to meet the threshold level set for study continuation and efficacy. Nevertheless, observed OR and prolonged stable disease in merits further evaluation.

“Trials in progress” posters

Phase I study of single-agent perifosine for recurrent pediatric solid tumors. (Becher et al)  J Clin Oncol 28:7s, 2010 (suppl; abstr 9540)

Perifosine is a synthetic alkylphospholipid which inhibits Akt activity. Single agent trials of perifosine in adults have demonstrated responses in patients with renal cell carcinoma, advanced brain tumors, soft-tissue sarcomas, hepatocellular carcinoma, as well as in hematologic malignancies including multiple myeloma. Pediatric patients with recurrent solid tumors were enrolled and 9 pts with high-grade glioma (n=5), medulloblastoma (n=2) or neuroblastoma (n=2) have been treated to date.  Perifosine is well tolerated in children with advanced solid tumors. The poster showed 2 patients with NB had stable disease 48 weeks and 55+ weeks, and dose level 4 is open. This study opened in 2008, with planned accrual 36. Another study with perifosine and temsirolimus just opened as well. The discussant mentioned the difficulty of completing accrual for this single-agent trial when a combination trial using this drug is open at the same institution.

A phase I trial of TPI-287 as a single agent and its combination with temozolomide in relapsed neuroblastoma or medulloblastoma. (Sholler et al) J Clin Oncol 28:7s, 2010 (suppl; abstr TPS329)

A novel anti- microtubule agent, TPI 287, is synthetically manufactured from naturally occurring taxanes extracted from yew starting material. The synthesis involves modifications of the side chain to make the drug more lipophilic, and modification of the baccatin ring structure which circumvents multidrug resistance (MDR)-based resistance and allows for binding to mutant tubulin. The primary objective is to determine the safety, tolerability and maximum tolerated dose (MTD) of TPI 287. The secondary objectives are to examine the activity of TPI 287 as a single agent and in combination with temozolomide (TMZ) in these tumor types based on overall response rate (ORR), progression free survival (PFS), and median overall survival (OS) and to evaluate the pharmacokinetics (PK) of TPI 287. There are 4 dose level escalations with the MTD of single agent therapy defined as the dose level below which DLTs are seen in ≥ two of six patients dosed.

Rather than posting everything at once, I’ll cover a topic or two for each post.

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Vaccines for neuroblastoma

The two talks at ASCO that touched upon the concept of vaccines were on cellular therapies by Lawrence Cooper from MD Anderson, and immunotherapies by Alice Yu from San Diego in the Education Session. They reviewed the “state of the art” for these therapies, but no specifics on current or upcoming trials.

Backing up a bit, it is impressive to see how much work has been done in this arena with a focus on neuroblastoma. Pubmed brings up 175 articles, 27 reviews, and 60 free full text articles on “vaccine AND neuroblastoma.” I wonder with such a proliferation of vaccine products that have been developed for neuroblastoma how they ever prioritize testing these vaccines in children. The other question is, if so much work has been done, why are we still waiting for an effective vaccine? At the end of this post, this question is addressed.

There are only 5 clinical trial results published for vaccines given to children with neuroblastoma. As expected, vaccines work ideally in those with no detectable disease, and better in first remission than subsequent remissions. There is a challenge though in interpreting the results of these trials because it is too early for them to report long follow-up. How do we know if it works if a child is in a first remission and stays in remission? How do we know if they would have stayed in remission anyway, without the vaccine? In these studies “surrogate” markers are recorded as evidence of vaccine activity but the relationship between persisting activity to permanent remission is unknown. A vaccine may generate a whopping initial immune response to the NB, but then fade quickly away. The only way to get a solid idea of the lasting effectiveness of a vaccine is to give it to several children in second remission and see how long they survive without relapsing again, or in a randomized trial just like the ch14.18 which showed better outcome in the group that got the ch14.18.

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Current clinical trials and future promise

To summarize, the job is not done. As quote above, the theoretical basis is sound, and some of the animals studies produce astounding cures (see a recent study using poliovirus curing mice[7]), but the truth is that the tumor cell can be camouflaged so easily as “self” because the origin IS self. Vaccines against viruses and other evils originate elsewhere and that is why maintaining “immune memory” is so much easier.

Open trials are underway at:

• Memorial Sloan-Kettering using an allogeneic bivalent vaccine (for remission after relapse)
• Penn State using an autologous vaccine (frontline therapy)
• National Institutes of Health (NIH) using autologous tumor lysate/pulsed dendritic cell vaccine (relapse/refractory)
• Baylor/Texas Children’s using allogeneic CHESAT vaccine (frontline therapy)

Contact the principal investigator for the current status of the trial.

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References:

1. Phase I trial of vaccination with autologous neuroblastoma tumor cells genetically modified to secrete IL-2 and lymphotactin.  J Immunother. 2007 Feb-Mar;30(2):227-33.PMID: 17471169

2. A phase 1/2 study of autologous neuroblastoma tumor cells genetically modified to secrete IL-2 in patients with high-risk neuroblastoma.  J Immunother. 2008 Nov-Dec;31(9):812-9.PMID: 18833006

3. Results of a Phase I study utilizing monocyte-derived dendritic cells pulsed with tumor RNA in children with Stage 4 neuroblastoma. Cancer. 2005 Mar 15;103(6):1280-91.PMID: (free fulltext) 15693021

4. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood. 2003 Mar 1;101(5):1718-26. Epub 2002 Oct 24.PMID: 12406881

5. Depletion of CD4 T cells enhances immunotherapy for neuroblastoma after syngeneic HSCT but compromises development of antitumor immune memory. Blood. 2009 Apr 30;113(18):4449-57. Epub 2009 Jan 30. (free fulltext) PMID: 19182203

6. Failure of cancer vaccines: the significant limitations of this approach to immunotherapy. Anticancer Res. 2000 Jul-Aug;20(4):2665-76.  PMID: 10953341

7. Oncolytic treatment and cure of neuroblastoma by a novel attenuated poliovirus in a novel poliovirus-susceptible animal model. Cancer Research 67, 2857, March 15, 2007. PMID: 17363609

The 2010 ASCO meeting is in full swing.  Attending a meeting with more than 30,000 cancer specialists from around the world is an incredible experience and provides an unparalleled opportunity to learn about cancer. The organization, logistics, and technology displayed are absolutely mind boggling. The vast exhibitor hall has spectacular booths set up by every pharmaceutical company ever heard of. There are 350 patient advocates here–and the vast majority are focused on adult cancers. On my first shuttle ride to the conference I visited with a charming adult oncologist from Slovakia, on the return trip I chatted with a lovely young French-speaking oncologist from Montreal. The whole city of Chicago appears to be populated by oncologists!

To say the meeting is overwhelming is an understatement. I decided to purchase the Virtual Meeting as well so I can review the sessions I have heard, as well as see other presentations happening simultaneously. This means that there will be ample opportunity to carefully review the material and update this site with much more meaningful information over the next few weeks.

Day 1 and Day 2 consisted of the following presentations (termed Education Sessions).

Childhood Cancer Survivorship: Lessons Learned and Future Steps
Kevin C. Oeffinger, MD
~ Current guidelines for follow up of the survivors of pediatric cancers.
Current new areas of research including issues related to genetic
susceptibility to toxicities
Smita Bhatia, MD, MPH
~ Long-term psycho-social effects following the treatment of pediatric
cancers.
Christopher Recklitis, MPH, PhD
~ Discussion of the Childhood Cancer Survivor Study (CCSS)
Gregory T. Armstrong, MD, MSCE

Current Challenges for Cellular Therapies
~ When should immunablative therapies be considered in the treatment of
pediatric cancer?
John M. Cunningham, MBBS
~ Adoptive cellular therapies utilizing gene modified lymphocytes
Laurence Cooper, MD, PhD
~ The role of NK cells in transplant and the non-transplant scenario
Wing H. Leung, MD, PhD

The Expanding Role of Antibody-based Therapy in Children,
Adolescents, and Young Adults with Cancer
~ Progress in treatment of high-risk neuroblastoma with immunotherapy
Alice L. Yu, MD, PhD
~ Update on Immunotherapy Strategies in the Treatment of Lymphomas in
children, adolescents and young adults
Mitchell S. Cairo, MD
~ The efficacy of epitope-specific IGFR1 antibodies in therapy of pediatric,
adolescent and young adult solid tumors
Douglas Yee, MD

New Treatments for Sarcoma in Children, Adolescents, and Young Adults
~ Optimal approaches for achieving local control in children, adolescents, and
young adults with sarcoma
R. Lor Randall, MD, FACS
~ Optimal strategies for controlling metastatic disease in children,
adolescents, and young adults with sarcoma
Douglas S. Hawkins, MD
~ Treatment of childhood, adolescent, and young adult sarcoma. Where do
we go from here?
Stephen X. Skapek, MD

Last session today was a terrific presentation on how pediatric oncology clinical trials serve as a model for “comparative effectiveness research.” More on this later.

Brief comments on sessions so far:

Genetic predisposition for heart damage in some children

The most important finding shared about late effects was the genetic mutations discovered that predispose a child for cardiotoxicity from low-dose anthracyclines, and this is significant for NB parents because almost all NB kids get doxorubicin as part of induction. There is consideration now of testing children in future trials for the mutations, and if one is found, reducing or eliminating anthracyclines from frontline therapy, or using a cardioprotectant. Further information will be presented on this topic on Monday morning session.[1]

Reduced-intensity allogeneic transplants and NK and T cell therapies

The discussion on reduced intensity transplant was really interesting and I look forward to looking at the data more closely. Many studies in adults have been completed for different diseases, and most show lower toxicity and better survival. Tomorrow there is a poster presentation on a study from Italy in NB kids. I will follow up with data and referenced studies. There has been so much work on NK cell therapies it is very exciting to see the possibilities emerging for NB. If you do a search for NK cell therapies on the National Institutes of Health site (www.clinicaltrials.gov) there are more that 200 open trials for various cancers. Memorial Sloan-Kettering is currently accruing for their NK cell therapy trial, but this trial was not discussed in any detail. MD Anderson also has an open Phase II study using donor NK cells for those who relapse or are refractory after stem cell transplant. Several papers have been recently published and after reviewing them I can report more fully on this topic. It was encouraging to hear the discussant Dr Leung say that he sees NK cells as an ideal treatment after frontline induction and consolidation, before antibody treatment. He believes this could be the next big jump in survival for frontline therapy.[2]

Antibody update

Dr Yu gave an excellent presentation updating on all things anti-GD2. She reviewed the history of all antibodies for NB, and said that two humanized antibodies (hu14.18-IL2 and hu14.18K332A) and a new anti-iodiotype antibody 1A7 are all considered for future trials. The 1A7 is interesting because it works like a vaccine. Instead of injecting antibodies into a child, this antibody induces the production of antibodies against GD2 continuously. After the session I asked her about the supply of ch14.18. The supply is good for two years since NCI made two more “batches” and a manufacturer has committed to produce the ch14.18. Then we discussed the trouble in the UK with access to GM-CSF for use with the ch14.18 antibody, and she said that she was going to speak to the Genzyme representative since they recently “inherited” the drug. Later I went to talk to Genzyme too. Genzyme said that there are regulatory issues with the UK (not the US) that prohibit the importing of the drug. He said to tell families interested in working with their doctor to contact Idis (www.idispharma.com) because Idis is an expert in getting access to drugs. They developed a program called Named Patient Program (see http://idispharma.com/patients.php ) to help gain access to drugs blocked by regulatory hurdles. Another question I have though, and could not be answered yet, is will SIOP rewrite the protocol to include GM-CSF? Dr Yu mentioned they are currently using IL2 (subcutaneously). Perhaps this can be further clarified for us by the families in the UK who are on the SIOP trial. Another question I have is whether the access to GM-CSF affects the other countries in Europe.

1.  J Clin Oncol 28:7s, 2010 (suppl; abstr 9512)

2.  Leung, Wing. The Role of Natural Killer Cells in Transplant and the Nontransplant Scenario. ASCO 2010 Educational Book, p 377-381