for Stage IVs running out of options, a vaccine trial with hopeful results

[Lani]

(not her2 specific)


Vaccine May Slow Advance of Breast, Ovarian Cancers


This report is part of a 12-month Clinical Context series.
By Kurt Ullman, Contributing Writer, MedPage Today
Published: November 08, 2011
Reviewed by Vandana G. Abramson, MD; Assistant Professor of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.

Note that in this pilot study of 26 patients with advanced breast or ovarian cancer, a recombinant poxviral vaccine resulted in a decrease in serum tumor markers and/or stable disease in a subset of patients.
Ovarian and breast cancer patients with limited tumor burden and minimal prior chemotherapy may benefit from a recombinant poxviral vaccine, according to researchers with the National Cancer Institute (NCI).
Among 12 patients with breast cancer who were given the vaccine, median time to progression was 2.5 months (range: 1 to 37+ months) with a median overall survival of 13.7 months (range: 2.7 to 42.9), reported James L. Gulley, MD, and colleagues from the Laboratory of Tumor Immunology and Biology at NCI.

For 14 ovarian cancer patients who received the vaccine, median time to progression was two months (range: 1 to 6 months) with median overall survival of 15.0 months (range: 1.5 to 57+ months), the authors wrote in the Nov. 15 edition of Clinical Cancer Research.

The 26 patients in the trial had either metastatic breast (n=12) or ovarian cancer (n=14) which had progressed following standard therapy, or they were patients who were not candidates for standard therapies. Enrollees also were required to have an Eastern Cooperative Oncology Group performance status of 0 or 1.

Participants were given monthly injections with PANVAC vaccines expressing tumor-associated antigens (TAA) for carcinoembryonic antigen (CEA) and mucin-1 along with three T-cell costimulatory molecules.

These patients were also heavily pretreated. Of the 26 patients, 21 had three or more previous rounds of chemotherapy.

Side effects were generally mild. Injection-site reactions were most commonly reported.

Among the breast cancer patients, five started the trial with elevated serum CEA levels, with two showing a decrease. Four of the patients had stable disease.

Among the ovarian cancer patients, two showed declines in serum CA-125, an antigen found on the surface of many ovarian cancer cells,

"In the study reported here, some patients who had limited tumor burden and whose immune system was not compromised by multiple rounds of chemotherapy seemed to benefit from the vaccine," the authors wrote.

They also noted that some patients showed good clinical responses to subsequent therapies following the study. This suggests that once a vaccine triggers a response from the immune system, it may start a "prolonged, dynamic process" that could lead to increased responses to any following therapy.

Many of the patients had already progressed by their first scheduled restaging. The researchers pointed out that previous studies have shown a lag of at least a few months before an optimal immune response.

Therefore, they theorized, reported progression may not reflect the effect of the vaccine, but an ongoing process before the immune system has had an adequate time to ramp up a response. They suggested that overall survival may be a better endpoint than time to progression or tumor shrinkage.

Gulley and colleagues stressed that this was a pilot study, but did say that their results confirm that other studies are warranted.

No potential conflicts of interest were disclosed by the authors.



Primary source: Clinical Cancer Research
Source reference:
Mohebtash M, et al "A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer" Clin Cancer Res 2011; 17(22): 1-10.

[Rich66]

Clin Cancer Res. 2011 Nov 8. [Epub ahead of print]
A Pilot Study of MUC-1/CEA/TRICOM Poxviral-Based Vaccine in Patients with Metastatic Breast and Ovarian Cancer.

Mohebtash M, Tsang KY, Madan RA, Huen NY, Poole DJ, Jochems C, Jones J, Ferrara T, Heery CR, Arlen PM, Steinberg SM, Pazdur M, Rauckhorst M, Jones EC, Dahut WL, Schlom J, Gulley JL.
Source

Authors' Affiliations: Medical Oncology Branch and Laboratory of Tumor Immunology and Biology, Center for Cancer Research; Biostatistics and Data Management Section, National Cancer Institute; and Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, Maryland.

Abstract

PURPOSE:

PANVAC is a recombinant poxviral vaccine that contains transgenes for MUC-1, CEA, and 3 T-cell costimulatory molecules. This study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients.Experimental design: Twenty-six patients were enrolled and given monthly vaccinations. Clinical and immune outcomes were evaluated.
RESULTS:

These patients were heavily pretreated, with 21 of 26 patients having 3 or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1-37+) and median overall survival was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST and remained on study for 37 months or more, with a significant drop in serum interleukin (IL)-6 and IL-8 by day 71. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. For the ovarian cancer patients (n = 14), the median time to progression was 2 months (1-6) and median overall survival was 15.0 months. Updated data are presented here for one patient treated with this vaccine in a previous trial, with a time to progression of 38 months.
CONCLUSIONS:

Some patients who had limited tumor burden with minimal prior chemotherapy seemed to benefit from the vaccine. Further studies to confirm these results are warranted. Clin Cancer Res; 17(22); 1-10. ©2011 AACR.

PMID:22068656 [PubMed - as supplied by publisher]



http://www.cancernetwork.com/breast-.../10165/1988943

“I think the reason we haven’t seen many responses is because the patient populations we've used in the past were too advanced, and had too many prior chemotherapy regimens. In addition, I think that the main activity of a therapeutic vaccine may be to eventually slow down the growth rate of cancers. [A response is caused in relatively few patients.] A delay in the slowing of the growth rate may be due to continued refinement and broadening of the immune response following vaccination. This could explain why multiple randomized studies have shown an improved overall survival without initial improved time to progression,” said Gulley.
This trial, and especially the over 3-year sustained response of a patient with advanced breast cancer shows the potential of a therapeutic vaccine for improved outcomes in a selective subset of patients

Somewhat similar to benefit of Herceptin beyond progression?

Makes me wonder whether other vaccine trials may have been prematurely deemed failures...



Here's some fun looking at variations in headlines:

Researchers claim small victory from experimental cancer vaccine‎

Vaccines for Breast and Ovarian Cancer Yield Triumphant Results‎

[Ellie F]

It feels like we are getting nearer with vaccines but maybe not quite there yet! The tumour vaccine group have been developing vaccines for many years and I understand that they believe they have now got a very effective her 2 peptide vaccine. The problem still seems to be how to maintain the immune response ,if indeed you can overcome tolerance.

Ellie

[Rich66]

from above excerpt: "multiple randomized studies have shown an improved overall survival without initial improved time to progression,"

So..could it be possible that some of these "failed" vaccines would yield better results if continued past progression? It seems the RECIST (near term shrinkage etc) criteria may not be up to the task of evaluating immune based therapies.

[Rich66]

another immune approach that makes me wonder if continuation might give better results:

J Immunol. 2011 Nov 2. [Epub ahead of print]
Pilot Clinical Trial of Type 1 Dendritic Cells Loaded with Autologous Tumor Lysates Combined with GM-CSF, Pegylated IFN, and Cyclophosphamide for Metastatic Cancer Patients.

Alfaro C, Perez-Gracia JL, Suarez N, Rodriguez J, Fernandez de Sanmamed M, Sangro B, Martin-Algarra S, Calvo A, Redrado M, Agliano A, Gonzalez A, Rodriguez I, Bolaños E, Hervás-Stubbs S, Perez-Calvo J, Benito A, Peñuelas I, Vigil C, Richter J, Martinez-Forero I, Melero I.

LINK

Source

Gene Therapy and Hepatology Unit, Center for Applied Medical Research, University of Navarra, 31008 Pamplona, Spain;

Abstract

Twenty-four patients with metastatic cancer received two cycles of four daily immunizations with monocyte-derived dendritic cells (DC). DC were incubated with preheated autologous tumor lysate and subsequently with IFN-α, TNF-α, and polyinosinicolycytidylic acid to attain type 1 maturation. One DC dose was delivered intranodally, under ultrasound control, and the rest intradermally in the opposite thigh. Cyclophosphamide (day -7), GM-CSF (days 1-4), and pegIFN alpha-2a (days 1 and 8) completed each treatment cycle. Pretreatment with cyclophosphamide decreased regulatory T cells to levels observed in healthy subjects both in terms of percentage and in absolute counts in peripheral blood. Treatment induced sustained elevations of IL-12 in serum that correlated with the output of IL-12p70 from cultured DC from each individual. NK activity in peripheral blood was increased and also correlated with the serum concentration of IL-12p70 in each patient. Circulating endothelial cells decreased in 17 of 18 patients, and circulating tumor cells markedly dropped in 6 of 19 cases. IFN-γ-ELISPOT responses to DC plus tumor lysate were observed in 4 of 11 evaluated cases. Tracing DC migration with [(111)In] scintigraphy showed that intranodal injections reached deeper lymphatic chains in 61% of patients, whereas with intradermal injections a small fraction of injected DC was almost constantly shown to reach draining inguinal lymph nodes. Five patients experienced disease stabilization, but no objective responses were documented. This combinatorial immunotherapy strategy is safe and feasible, and its immunobiological effects suggest potential activity in patients with minimal residual disease. A randomized trial exploring this hypothesis is currently ongoing.

PMID:22048768 [PubMed - as supplied by publisher]



Especially in light of this:




J Immunol. 2011 Oct 15;187(8):4109-18. Epub 2011 Sep 9.
Chronic chemoimmunotherapy achieves cure of spontaneous murine mammary tumors via persistent blockade of posttherapy counter-regulation.

Rowswell-Turner RB, Harden JL, Nair RE, Gu T, Kilinc MO, Egilmez NK.

LINK

Source

Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214,USA.

Abstract

Intratumoral delivery of IL-12 and GM-CSF induces local and systemic antitumor CD8(+) T cell activation and tumor kill. However, the effector response is transient and is rapidly countered by CD4(+) Foxp3(+) T suppressor cell expansion. To determine whether depletion of the pre-existing T suppressor cell pool prior to treatment could diminish posttherapy regulatory cell resurgence, FVBneuN mice bearing advanced spontaneous mammary tumors were treated with cyclophosphamide (CY) 1 d before IL-12/GM-CSF therapy. Administration of CY mediated a significant delay in the post-IL-12/GM-CSF T suppressor cell rebound, resulting in a 7-fold increase in the CD8(+) CTL/T suppressor cell ratio, a 3-fold enhancement of CTL cytotoxicity, and an extension of the effector window from 3 to 7 d. In long-term therapy studies, chronic chemoimmunotherapy promoted a dramatic enhancement of tumor regression, resulting in complete cure in 44% of the mice receiving CY plus IL-12/GM-CSF. Tumor eradication in the chronic therapy setting was associated with the ability to repeatedly rescue and maintain cytotoxic CD8(+) T cell activity. These findings demonstrated that chronic administration of CY in conjunction with immune therapy enhances the initial induction of antitumor T effector cells and, more importantly, sustains their cytotoxic activity over the long-term via persistent blockade of homeostatic counter-regulation.



And the approach of using Cytoxan to suppress undesirable immune responses keeps coming up...making me wonder if the PANVAC trial could have done better with some Cy in the mix.

Maybe it would help Herceptin.