Ann: Science Series CHECKvacc, page-134

Hi Mason,

Thanks for your post re CHECKvacc results in TNBC.

Not sure if you are aware, but I thought I would share an update to these results presented at ESMO 2023 in Madrid

At the ESMO Congress 2023 held in Madrid, researchers presented intriguing findings related to the treatment of metastatic triple-negative breast cancer (mTNBC).

• Study Title: Induction of an Inflammatory Tumor Microenvironment with Oncolytic Virus CF33-hNIS-antiPD-L1 Intratumoral Injection in Patients with Metastatic Triple-Negative Breast Cancer (mTNBC) ¹.

• Background:

  • The investigational agent is CF33-hNIS-anti-PD-L1 (CHECKvacc), a novel chimeric orthopoxvirus.
  • Previous studies demonstrated that CHECKvacc has robust anti-cancer activity in TNBC xenografts.
  • CHECKvacc enhances CD8+ T cell infiltration and favorably modulates the tumor microenvironment (TME) in xenograft models ¹².

• Clinical Trial Details:

  • Phase: I
  • Design: Single-center, single-arm trial
  • Eligibility Criteria:
    • Patients with mTNBC who progressed on ≥ 2 chemotherapy regimens.
    • At least 1 tumor amenable to intratumoral (IT) injections.
  • Treatment Regimen:
    • CHECKvacc IT injections administered at 1 of 8 assigned escalating dose levels on Days 1 and 15 of each 28-day cycle for 3 cycles.
  • Primary Objective: Evaluate safety and tolerability.
  • Secondary Objectives:
    • Determine recommended phase II dose.
    • Assess efficacy.
  • Exploratory Objectives:
    • Evaluate TME immune modulation.
    • Analyze PD-L1 expression using a combined positive score (CPS) ¹.

• Key Findings:

  • Safety: No dose-limiting toxicities observed.
  • Immune Modulation:
    • CD8+ T cells in the TME increased in 5 out of 6 patients from baseline to cycle 1 day 2 (median increase: 34%).
    • CD4+ T cells also increased in 4 out of 6 patients (median increase: 39%).
    • PD-L1 expression by CPS increased in 5 out of 6 patients (range of increase: 4-50%, p=0.063 by Wilcoxon signed-rank test).
  • Implications:
    • CHECKvacc induces tumor infiltration of CD4+ and CD8+ T cells.
    • Upregulation of PD-L1 within the TME suggests immune activation by CHECKvacc.
    • Ongoing clinical trial to assess dose escalation, tumor response, and potential combination trials with systemic therapies (e.g., checkpoint blockade and chemotherapy) ¹.

These findings highlight the promising potential of CHECKvacc in reshaping the tumor microenvironment and enhancing immune responses in mTNBC patients. Further investigations will shed light on its clinical applicability and combination strategies for improved outcomes.

And Mason I am not sure if you are aware but there is this intriguing post from @davybabyk posted on 14/11/2023
https://hotcopper.com.au/posts/70880185/single

"Good morning all

An EXTREMELY interesting case study just appeared online in the journal "Therapeutic Advances in Medical Oncology." The publication date is 10 Nov but I think it only appeared overnight. For me - this warrants a price sensitive announcement by IMU.

Yuman Fong is co-author, along with Dr Yuan Yuan who was initially r running the Check-vacc trial at CoH. I will summarise the paper below. Pls note - I'm doing this in a huge rush. It deserves a longer explanation but I want to get this online.

The paper is a case study of a 74 year old woman with extensive metastatic Breast Cancer who started on the Checkvacc clinical trial, and received one dose of Check-vacc only at the very very low starting doe level of 1 x 10⁵ PFU (just 100,000 viral units). The poor woman had massive external skin lesions - there are very confronting photos in the journal paper.

After 15 days the lesions were more "erythematous" (Inflamed/red) and so she chose to discontinue treatment. ie she decided to drop out of the trial. I think the implication is she felt that the treatment was failing.

25 days after the Check-vacc injection, she then received a treatment of trastuzumab-deruxtecan. That's a combo treatment of trastuzumab (a monoclonal antibody) and Deruxtecan (a drug which block a specific enzyme).

The Result: A complete response - the lesions healed. The complete response lasted 7 months with a disease free survival of 10 months.

Now the BIG question: was this as a result of the trastuzumab-deruxtecan?

The researchers cannot be sure, but they point out a few key facts:

• There are no cases of the trastuzumab-deruxtecan achieving a complete response in a patient with metastatic breast cancer. ( "To date, no CR in a patient with HER2-zero metastatic BC receiving T-DXd has been reported."). So if this was a result of the trastuzumab-deruxtecan, it would be the fisrt time that has been seen. Reasonable "hypothesis" - the result was due to Check-vacc, or at least to the combo of check-acc with trastuzumab-deruxtecan.
• Before leaving the trial, the biopsies showed all the clinical markers and immune response expected from Check-vacc.
• The patient started the Check-vacc trial after around 7 prior failed lines of treatment. She was incredibly unwell.

After 10 months disease free, the poor woman did have a return of the cancer. The researchers note that "The return of disease within a year suggests that any tumor-specific memory induced by the treatments was not potent enough to prevent residual cancer cells from forming tumors. Future studies are necessary to better understand the mechanism of combination therapy with OV and ADCs."

However, remember that this person only received a single dose of Check-vacc - and it was at the extremely low level of 100,000 viral units. What Yuman described in his visit to Sydney and Melbourne as "Teeny Tiny doses."

Yes - she chose to drop out of the trial because the cancer lesions "looked" worse due to the red/inflamed colour - but the researchers point out the likelihood that this was pseudo-progression (as seen with the complete response on the Vaxinia trial).

Warning - of course - a single patient does not prove anything - but this is incredibly exciting and encouraging. The researchers clearly think so, and the peer rec=viewed journal of Therapeutic Advances in Medical Oncology has published the paper.

Read it for yourself here: https://journals.sagepub.com/doi/10.1177/17588359231210675

Apologies but I was unable to insert the link correctly

GLTAH - Go Team Imugene
.